Disease models and uses thereof

Abstract

A disease model and uses thereof. Specifically, a model of a nervous system disease or condition is provided, the model comprising and / or expressing an intron retention cleavage product or fragment thereof of a DNA damage-induced transcript 4-like transcript.

Description

Disease models and their applications Technical Field This application relates to a disease model and its uses. In particular, this application relates to a model of neurological diseases or conditions and its uses. Background Technology my country's aging population is increasing year by year. Due to factors such as weakened immunity and arteriosclerosis, the elderly face a variety of diseases, among which cognitive impairment and neurodegenerative diseases (such as Alzheimer's disease) account for a significant proportion of the current elderly population. Therefore, developing therapeutic drugs for these conditions is of paramount importance. A major obstacle in research on such neurological diseases or conditions is the lack of suitable animal models. Currently reported are transgenic mouse models that overexpress amyloid precursor protein (APP), such as the Tg2576 mouse (Science, 274:99-102 (1996)) and other APP mouse models. However, these APP-overexpressing animal models often fail to reproduce the disease progression and pathological features of human patients, making the development of clinically effective therapeutics difficult or even impossible. Although more than 120 animal models have been established to study such neurological diseases or conditions (e.g., Alzheimer's disease (AD)), very few of them can truly reproduce all the neuropathological phenotypes seen in the corresponding human patients. More importantly, a considerable number of recent candidate therapies have shown efficacy in these animal models but failed in clinical trials. All these problems are likely due to the inherent limitations of such animal models. Therefore, there is an urgent need to develop a new disease model that is clinically relevant and more realistically reproduces the phenotype of human patients. Summary of the Invention This application provides a disease model and its uses. Specifically, this application provides a model of a neurological disease or condition that includes and / or expresses the intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or its functionally active fragments, which can be used as a research tool for neurological diseases or conditions. In one aspect, this application provides a non-human animal or a portion thereof comprising and / or expressing the intron-retained cleavage product DIR and / or a functionally active fragment of DNA damage-inducing transcript 4-like transcript (DDIT4L). In some embodiments, the DDIT4L is human DDIT4L. In some embodiments, the DDIT4L comprises the amino acid sequence shown in SEQ ID NO:3. In some implementations, the DIR is derived from a human being. In some embodiments, the DIR and / or its functionally active fragment comprises any one of SEQ ID NO: 1-2 and 4-5. The amino acid sequence shown. In some implementations, the gene encoding the DIR and / or its functionally active fragment is homozygous or heterozygous. In some embodiments, the gene encoding the DIR and / or a functionally active fragment thereof comprises a nucleic acid sequence shown in any one of SEQ ID NO:12-15. In some embodiments, the non-human animal is a gene-edited non-human animal, or is derived from a gene-edited non-human animal. In some embodiments, the non-human animal is a gene-knock-in non-human animal, or a non-human animal derived from a gene-knock-in non-human animal. In some embodiments, the expression of the DIR and / or its functionally active fragments is regulated by corresponding endogenous regulatory elements in the non-human animal genome. In some implementations, the non-human animal is a non-human mammal. In some embodiments, the non-human animal is selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats. In some embodiments, the non-human animal is a rodent or a primate. In some embodiments, the portion includes organs, tissues, and / or cells of the non-human animal. In some embodiments, the portion includes bodily fluids. In some embodiments, the body fluid is selected from the group consisting of blood, plasma, serum, urine, sweat, tears, saliva, semen, and cerebrospinal fluid. In some embodiments, the plasma includes exosomes. In some implementations, the portion includes the brain or a portion thereof. In some embodiments, the brain regions included in a portion of the brain are selected from the group consisting of: the olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, and cerebellum. In some embodiments, the portion includes the olfactory mucosa. In some embodiments, the portion includes a part of the central nervous system, a part of the peripheral nervous system, skin tissue, muscle tissue, and / or internal organs. In some embodiments, the central nervous system includes the spinal cord. In some embodiments, the portion includes cells, and the cells include cells selected from the group consisting of: primary neurons, microglia, astrocytes, oligodendrocytes, macrophages, perivascular epithelial-like cells, B cells, T cells, adult stem cells, NK cells, pluripotent stem cells, unipotent stem cells, embryonic stem cells, induced pluripotent stem cells, and gametes. In some embodiments, the gametes include sperm and / or oocytes. In some implementations, the portion cannot develop into a complete non-human animal. On the other hand, this application provides offspring or portions thereof of the non-human animal described in this application, which are obtained by hybridizing the non-human animal described in this application with another non-human animal, wherein the other non-human animal may or may not express the DIR and / or its functionally active fragments. In some implementations, the offspring or a portion thereof contains and / or expresses the DIR and / or its functionally active fragments. In some implementations, the portion is as described in other aspects of this application. On the other hand, this application provides an isolated cell. The cell contains and / or expresses the intron-retained cleavage product DIR of DNA damage-inducing transcript 4-like transcript (DDIT4L) and / or its functionally active fragments. In some embodiments of the cell, the DIR is derived from human. In some embodiments of the cell, the DIR and / or its functionally active fragment comprises the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5. In some embodiments of the cell, the gene encoding the DIR and / or its functionally active fragment is homozygous or heterozygous. In some embodiments of the cell, the gene encoding the DIR and / or a functionally active fragment thereof comprises a nucleic acid sequence shown in any one of SEQ ID NO:12-15. In some embodiments, the cells are gene-edited cells or derived from gene-edited cells. In some embodiments, the cell is a gene-knock-in cell or a cell derived from a gene-knock-in cell. In some embodiments of the cell, the expression of the DIR and / or its functionally active fragments is regulated by corresponding endogenous regulatory elements in the cell genome. In some embodiments, the cells are non-human animal cells. In some embodiments of the cell, the non-human animal is a non-human mammal. In some embodiments of the cell, the non-human animal is selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats. In some embodiments of the cell, the non-human animal is a rodent or a primate. In some embodiments, the cells include cells selected from the group consisting of neuroblastoma cells, glioma cells, primary neurons, microglia, astrocytes, oligodendrocytes, macrophages, perivascular epithelioid cells, B cells, T cells, adult stem cells, NK cells, pluripotent stem cells, unipotent stem cells, embryonic stem cells, induced pluripotent stem cells, and gametes. In some embodiments of the cell, the gametes include sperm and / or oocytes. In some implementations, the cells cannot develop into complete non-human animals. On the other hand, this application provides a tissue. The tissue comprises and / or expresses the intron-retained cleavage product DIR of DNA damage-inducing transcript 4-like transcript (DDIT4L) and / or its functionally active fragments. In some implementations of the organization, the DIR is derived from a human being. In some embodiments of the tissue, the DIR and / or its functionally active fragments comprise the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5. In some embodiments of the organization, the gene encoding the DIR and / or its functionally active fragments is homozygous or heterozygous. In some embodiments of the organization, the gene encoding the DIR and / or a functionally active fragment thereof comprises a nucleic acid sequence shown in any one of SEQ ID NO:12-15. In some implementations, the tissue is a gene-edited tissue or is derived from a gene-edited tissue. In some embodiments, the tissue is a gene-knock-in tissue or a tissue derived from a gene-knock-in tissue. In some embodiments of the tissue, the expression of the DIR and / or its functionally active fragments is regulated by corresponding endogenous regulatory elements in the tissue genome. In some embodiments, the tissue is non-human animal tissue. In some embodiments of the organization, the non-human animal is a non-human mammal. In some embodiments of the organization, the non-human animal is selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats. In some embodiments of the organization, the non-human animal is a rodent or a primate. In some embodiments, the tissue includes bodily fluids. In some embodiments of the organization, the body fluid is selected from the group consisting of blood, plasma, serum, urine, sweat, tears, saliva, semen, and cerebrospinal fluid. In some embodiments of the tissue, the plasma includes exosomes. In some embodiments, the tissue includes the brain or a portion thereof. In some embodiments of the organization, a portion of the brain includes brain regions selected from the group consisting of: the olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, and cerebellum. In some embodiments, the tissue includes the olfactory mucosa. In some embodiments, the tissue includes a portion of the central nervous system, a portion of the peripheral nervous system, skin tissue, muscle tissue, and / or visceral organs. In some embodiments of the organization, the central nervous system includes the spinal cord. In some implementations, the tissue cannot develop into a complete non-human animal. On the other hand, this application provides a cell line or cell culture derived from the non-human animal or part thereof described in this application, derived from the offspring described in this application, derived from the cells described in this application, and / or derived from the tissues described in this application. In some embodiments, the cell culture is a primary cell culture. In some embodiments, the cell culture includes organoids. On the other hand, this application provides a composition. The composition comprises the non-human animal or a portion thereof described in this application, its offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application. On the other hand, this application provides a kit. The kit comprises the non-human animal or part thereof described in this application, the progeny described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application; and one or more additional components selected from the group consisting of: analytical buffers, controls, substrates, standards, detection materials, laboratory supplies, equipment, instruments, cells, organs, tissues, and a user manual or instruction manual. On the other hand, this application provides a method for screening and / or identifying substances, devices, and / or compositions for treating, preventing, and / or prognosing neurological diseases or conditions, the method comprising applying candidate substances, devices, and / or compositions to non-human animals or portions thereof described in this application, progeny described in this application, cells described in this application, tissues described in this application, and / or cell lines or primary cell cultures described in this application, and determining the effect of the candidate substances, devices, and / or compositions on one or more indicators of the neurological disease or condition. On the other hand, this application provides a method for designing substances, devices, and / or compositions for treating, preventing, and / or prognosing neurological diseases or conditions, the method comprising: (i) applying candidate substances, devices, and / or compositions to a non-human animal or part thereof described in this application, a progeny described in this application, a cell described in this application, a tissue described in this application, and / or a cell line or primary cell culture described in this application; (ii) determining the effect of the candidate substances, devices, and / or compositions on one or more indications of the neurological disease or condition; (iii) selecting candidate substances, devices, and / or compositions capable of preventing, inhibiting, and / or alleviating one or more of the indications of the neurological disease or condition; and (iv) modifying the structure and / or composition of the candidate substances, devices, and / or compositions of step (iii) to obtain modified substances, devices, and / or compositions having improved activity in treating, preventing, and / or prognosing the neurological disease or condition. In some embodiments of the method of this application, the neurological disease or condition includes cognitive impairment. In some embodiments of the method of this application, the nervous system disease or condition includes neurodegenerative diseases or conditions. In some embodiments of the method of this application, the neurological disease or condition includes mild cognitive impairment (MCI) and / or Alzheimer's disease. In certain embodiments of the method of this application, one or more indicators of the neurological disease or condition include: expression and / or accumulation of Aβ; expression and / or accumulation of APP fragments; phosphorylation of Tau protein; oligomerization and / or aggregation of Tau protein; changes in brain morphology and / or brain weight; formation of neurofibrillary tangles; changes in learning function, memory function, cognitive function, sensory function, motor function, emotional function and / or synaptic function; brain injury; neuronal loss, necrosome formation, neuronal death, changes in neuronal activity, neuronal apoptosis, neuronal necrosis, programmed neuronal cell death, number of Neu-N positive neurons and / or neurodegeneration; glial proliferation, microglia activation, astrocyte activation and / or inflammatory response; oxidative stress and / or mitochondrial dysfunction; vascular dysfunction; misfolded protein degradation and / or autophagy failure; and / or changes in brain glucose and / or lipid metabolism. In some embodiments of the method of this application, the accumulation of Aβ includes Aβ oligomerization and / or amyloid plaque formation. In some embodiments of the method of this application, the APP fragment includes: sAPP, CTF-β, CTF-a and / or AICD. In some embodiments of the method of this application, the synaptic function includes synaptic transmission, synaptic plasticity, formation and / or function of synaptic proteins, and / or synaptic morphology. In some embodiments of the method of this application, the inflammatory response includes a response by innate immune cells. In some embodiments of the method of this application, the innate immune cells include T cells, B cells, NK cells, macrophages, and / or dendritic cells. In some embodiments of the method of this application, the vascular dysfunction includes amyloid angiopathy and / or blood-brain barrier (BBB) ​​damage. In some embodiments of the method of this application, the apparatus includes a medical device. In some embodiments of the method of this application, the composition comprises a mixture derived from one or more organisms. In some embodiments of the method of this application, the organism includes plants, animals and / or microorganisms. In some embodiments of the method of this application, the composition comprises tissue homogenate and / or blood sample. On the other hand, this application provides a method for identifying potential biological targets and / or biomarkers that can be used to treat, prevent, and / or prognose neurological diseases or conditions, the method comprising: (i) performing quantitative or qualitative proteomics, lipidomics, and / or genomics comparative analysis on the non-human animal or part thereof described in this application, the offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application with corresponding controls; (ii) identifying genes, proteins, and / or lipids with altered sequences, contents, expression levels, modifications, and / or activities; (iii) wherein the genes, proteins, and / or lipids identified in step (ii) are potential biological targets and / or biomarkers that can be used to treat, prevent, and / or prognose the neurological diseases or conditions. On the other hand, this application provides a method for screening biological targets for diagnosing and / or monitoring neurological diseases or conditions. A method for identifying and / or identifying biomarkers, the method comprising: determining the presence and / or levels of substances in samples obtained from non-human animals or parts thereof, progeny thereof, cells thereof, tissues thereof, and / or cell lines or primary cell cultures thereof, respectively, before and after the occurrence of one or more related indicators of the neurological disease or condition, to identify substances whose presence and / or levels change before and after the occurrence of the indicators, and identifying such substances as the biological target and / or the biomarker. In certain embodiments of the method of this application, one or more indicators of the neurological disease or condition include: expression and / or accumulation of Aβ; expression and / or accumulation of APP fragments; phosphorylation of Tau protein; oligomerization and / or aggregation of Tau protein; changes in brain morphology and / or brain weight; formation of neurofibrillary tangles; changes in learning function, memory function, cognitive function, sensory function, motor function, emotional function and / or synaptic function; brain injury; neuronal loss, necrosome formation, neuronal death, changes in neuronal activity, neuronal apoptosis, neuronal necrosis, programmed neuronal cell death, number of Neu-N positive neurons and / or neurodegeneration; glial proliferation, microglia activation, astrocyte activation and / or inflammatory response; oxidative stress and / or mitochondrial dysfunction; vascular dysfunction; misfolded protein degradation and / or autophagy failure; and / or changes in brain glucose and / or lipid metabolism. In some embodiments of the method of this application, the neurological disease or condition includes cognitive impairment. In some embodiments of the method of this application, the nervous system disease or condition includes neurodegenerative diseases or conditions. In some embodiments of the method of this application, the neurological disease or condition includes mild cognitive impairment (MCI) and / or Alzheimer's disease. On the other hand, the use of the non-human animals or parts thereof described in this application, the offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application in the preparation of identification and / or screening systems for identifying and / or screening substances, devices, compositions, biological targets and / or biomarkers for the treatment, diagnosis, prevention, monitoring and / or prediction of neurological diseases or conditions. In some embodiments, the non-human animal or a portion thereof, the offspring, the cells, the tissues and / or the cell lines or primary cell cultures may be used to screen for substances, devices, compositions, biological targets and / or biomarkers for the treatment, diagnosis, prevention, monitoring and / or prediction of neurological diseases or conditions. On the other hand, this application provides a method for preparing the non-human animal or a portion thereof, the cell or tissue described in this application, the method comprising causing the non-human animal or a portion thereof, the cell or tissue to contain and / or express the DIR and / or its functionally active fragments. On the other hand, this application provides a method for preparing a disease model, the method comprising causing a non-human animal or a part thereof, cell or tissue to contain and / or express DIR and / or its functionally active fragments. In some embodiments of the method of this application, the disease is a neurological disease or condition. In some embodiments of the method of this application, the neurological disease or condition includes cognitive impairment. In some embodiments of the method of this application, the nervous system disease or condition includes neurodegenerative diseases or conditions. In some embodiments of the method of this application, the neurological disease or condition includes mild cognitive impairment (MCI) and / or Alzheimer's disease. In some embodiments of the method of this application, the DIR and / or its functionally active fragments comprise the amino acid sequences shown in any one of SEQ ID NO: 1-2 and 4-5. In some embodiments, the method includes knocking in a nucleic acid sequence encoding the DIR and / or a functionally active fragment thereof. In some embodiments of the method of this application, the nucleic acid sequence encoding the DIR and / or its functionally active fragment comprises the nucleic acid sequence shown in any one of SEQ ID NO:12-15. In some embodiments of the method of this application, the knock-in includes: in the presence of a donor nucleic acid molecule containing the nucleic acid sequence, contacting the genome of the non-human animal, cell, or tissue with: a CRISPR-associated (Cas) protein; and one or more ribonucleic acid (RNA) sequences, the RNA comprising: i) a portion complementary to the target site and ii) a binding site of the Cas protein. In some embodiments of the method of this application, the binding site of the Cas protein comprises a tracrRNA sequence. In some embodiments of the method of this application, the RNA sequence comprises the nucleic acid sequence shown in SEQ ID NO:6. In some embodiments of the method of this application, the knock-in further includes culturing the cells or tissues under conditions where the one or more RNA sequences hybridize with the target sequence, and the Cas protein cleaving the target sequence after the hybridization with the RNA sequence. In some embodiments of the method of this application, the Cas protein is Cas9. In some embodiments of the method of this application, the Cas protein is provided in the form of a protein, a messenger RNA (mRNA) encoding the Cas protein, or DNA encoding the Cas protein. In some embodiments of the method of this application, the one or more RNA sequences are provided in the form of one or more RNA molecules or one or more DNA molecules encoding the RNA sequence. Other aspects and advantages of this application will readily be apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this application are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the descriptions in the accompanying drawings and specification of this application are merely exemplary and not restrictive. Attached Figure Description The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows: Figure 1 shows an exemplary gene editing strategy used to prepare the disease model of this application. Figure 2 shows the validation results of the gene editing effect. Figure 3 shows exemplary phenotypic features of the disease model of this application. Figure 4 shows exemplary behavioral phenotypic features of the disease model of this application. Figure 5 shows exemplary physiological phenotypic features of the disease model of this application. Figure 6 shows that the growth, metabolism, and motor function of the disease model in this application were not altered. Figure 7 shows the DIR expression of the disease model in this application under hypoxic conditions. Figure 8 shows the effect of DIR antibody administration on cognitive levels in the disease model described in this application. Figure 8A, Y-maze test shows that working memory was reversed in homozygous DIR-KI mice (n=17) after treatment with the DIR antibody described in this application compared with IgG-treated mice (n=13). *, p<0.05. Figure 8B, In homologous DIR-KI mice (n=14), treatment with the DIR antibody described in this application reversed the ability to recognize novel objects compared with IgG-treated mice (n=11). **, p<0.01. Figure 8C, Morris water maze test shows that treatment with the DIR antibody described in this application (n=11) reduced escape latency after a 5-day training period compared with IgG treatment in homologous DIR-KI mice (n=9). In the detection test assessing spatial memory, IgG-treated mice did not show a preference for the target quadrant, while mice treated with the DIR antibody described in this application had shorter entry latency and spent more time in the target quadrant. *, p<0.05. Figure 8D shows the expression of Aβ and p-Tau in the dentate gyrus of the hippocampus of homozygous DIR-KI mice treated with DIR antibodies. Scale bar = 100 μm. Figure 8E shows that the expression of Aβ and p-Tau in the dentate gyrus of the hippocampus of homozygous DIR-KI mice treated with DIR antibodies was significantly reduced. *, p < 0.05.**, p < 0.01. Figure 8F shows that compared with IgG treatment, DIR antibody treatment significantly increased the LTP of field EPSP recorded in the CA1 region of the hippocampus of homozygous DIR-KI mice (n = 5 mice per group). Detailed Implementation The invention involved in this application is described below with specific embodiments. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification. In this application, the term "CRISPR" generally refers to clustered short-interval palindromic repeats. Regularly Interspaced Short Palindromic Repeats (SRSRs) are CRISPR gene loci that differ from other SSRs in the structure of their repeat sequences. These repeat sequences are called regularly interspaced short palindromic repeats (SRSRs). Generally, repeat sequences are short elements that appear in clusters with regular intervals and unique spacer sequences of essentially constant length. Repeat sequences are highly conserved across species, but the number of repeat sequences and the spacer sequences often differ between species. In this application, the terms "sgRNA," "guide RNA," "single guide RNA," and "synthetic guide RNA" are used interchangeably and generally refer to a polynucleotide sequence containing the guide sequence. The guide sequence is approximately 20 bp in length and is located within the guide RNA at the designated target site. In this application, the term "heterologous nucleic acid sequence" generally refers to a nucleic acid sequence that is exogenous and / or exists in a non-endogenous form. For example, a heterologous nucleic acid sequence may originate from other individuals, may originate from alien species, may be artificially synthesized, may be located at other non-endogenous loci, and / or may be significantly modified or altered. In this application, the term "homologous recombination" generally refers to genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA molecules (referred to as homologous sequences or homologous arms). In this application, the term “CRISPR-associated protein 9” or “Cas9” generally refers to an RNA-guided DNA endonuclease associated with the CRISPR (aggregated, regularly spaced short palindromic repeats) type II adaptive immune system found in certain bacteria, such as Streptococcus pyogenes and other bacteria. For example, the Cas9 protein may include not only the wild-type Cas9 found in Streptococcus pyogenes, but also its various variants, such as those described in WO2013 / 176772A1. In some embodiments, the Cas9 protein may comprise Cas9 sequences from Streptococcus pyogenes, Neisseria meningitidis, Streptococcus thermophilus, and Mycobacterium dentinatum, as described in Esvelt et al., Nature Methods, 10(11): 1116-1121, 2013. In this application, the term "Cas9 coding sequence" generally refers to a polynucleotide sequence capable of being transcribed and / or translated according to the genetic code in a host cell / host animal to produce a Cas9 protein. The Cas9 coding sequence can be DNA (such as a plasmid) or RNA (such as mRNA). In this application, the term "Cas9 riboprotein" generally refers to a protein / RNA complex consisting of the Cas9 protein and associated gRNA. In this application, the term "CRISPR / Cas9 system" generally refers to a tool for site-specific genome targeting in organisms. For example, it could be a type II CRISPR / Cas system, which is a system that uses non-coding RNA to guide Cas9 nucleases to induce site-specific DNA breaks. This DNA damage can be repaired by cellular DNA repair mechanisms, or through the non-homologous end joining DNA repair pathway (NHEJ) or homology-directed repair (HDR). The CRISPR / Cas9 system can be used to create a simple RNA-programmable method to mediate genome editing in mammalian cells and can be used to generate gene knockouts (via insertion / deletion) or knock-ins (e.g., via HDR). In this application, the term "knocking-in" or "knock-in" generally refers to a gene modification process that involves replacing DNA sequence information at a specific locus or inserting a foreign sequence into an endogenous locus. The knock-in may involve inserting a gene sequence into a specific site, and therefore can be a "targeted" insertion. In this application, the term "vector" generally refers to a DNA molecule used as a vector that is artificially introduced or carried into another cell or host and can be replicated and / or expressed in said cell or host. In this application, the term "targeting vector" generally refers to a vector carrying a target sequence for insertion into or incorporation into the host genome and / or replacement of endogenous DNA fragments. In this application, the terms "embryonic stem cells" or "ES cells" generally refer to pluripotent stem cells derived from the inner cell mass (ICM) of the blastocyst (an early preimplantation embryo in mammals), which, after being cultured in vitro and then embedded / injected into the cavity of a normal blastocyst, can be induced to resume normal embryonic developmental procedures to differentiate into various cell types, including germ cells, in adult animals. In this application, the term "zygote" generally refers to a eukaryotic cell formed by a fertilization event between gametes (such as eggs and sperm in mammals). In this application, the terms “homozygote” or “homozygous” are used for a specific gene or DNA (e.g., a knock-in heterologous nucleic acid sequence) and refer to a diploid cell or organism in which two homologous chromosomes have the same allele or gene / DNA copy. In this application, the terms “heterozygote” or “heterozygous” are used for a specific gene or DNA (e.g., a knock-in heterologous nucleic acid sequence) and refer to a diploid cell or organism in which two homologous chromosomes have different alleles / copies / versions of a gene or DNA. The term "no significant difference" as used in this article generally means that the difference between two values ​​or two objects is not substantial. For example, when comparing two values, if the difference is less than about 10%, such as less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5.5%, less than about 5%, less than about 4.5%, less than about 3.5%, less than about 3.5%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1%, or even lower, it can be considered as no significant difference. In this application, the term "Aβ oligomer" generally refers to aggregates of soluble amyloid β (Aβ) peptides that typically form clumps or plaques. Aβ oligomers can be dimers, trimers, or other polymers of the Aβ peptide. In this application, the terms “Aβ plaque” or “amyloid plaque” generally refer to fibrous aggregates of Aβ peptides (e.g., Aβ42 and / or Aβ40), wherein many copies of the Aβ peptide agglomerate together to form fibers or fibrous deposits (e.g., plaques). In this application, the term "massive accumulation of Aβ peptides" generally refers to the formation of Aβ oligomers or amyloid plaques that can be detected using common detection methods or tools, such as staining with a specific Aβ antibody. In this application, the term "Aβ" or "amyloid β" generally refers to the intramembrane protein water of amyloid precursor protein (APP). The amyloid-β peptide produced by cleavage. A successive proteolytic reaction of β- and γ-secretases produces Aβ peptides of varying lengths, including Aβ40 and Aβ42. Two superhydrophobic residues make Aβ42 more prone to aggregating into soluble oligomers and insoluble deposits. Aβ exists in various aggregation forms, from dimers to β-sheet-like fibers in dense neuritis plaques. Excessive Aβ can induce a variety of pathological processes. Aβ can impair neuronal and glial cell function, synaptic physiology, neurotransmission, and cognitive function. In this application, the term "hyperphosphorylation" or "overphosphorylation" refers to a state of abnormal phosphorylation at one or more sites. For example, phosphorylation of Tau protein has been found to negatively regulate its activity in promoting microtubule assembly, and abnormally hyperphosphorylated Tau is considered a major component of PHFs in Alzheimer's disease (AD) patients. Normal brain contains 2-3 moles of phosphate per mole of Tau. Studies of human brain biopsy tissues have shown that some serine and threonine residues of Tau are normally phosphorylated at low substoichiometric levels. The phosphorylation level of Tau isolated from autopsies of Alzheimer's disease (AD) patients is 3-4 times higher than that of normal human brains. Phosphorylation of Tau at different sites has different effects on its biological function and pathogenicity. Studies on the binding of hyperphosphorylated Tau to normal Tau have shown that Ser199 / Ser202 / Thr205, Thr212, Thr231 / Ser235, Ser262 / Ser356, and Ser422 are key phosphorylation sites. Phosphorylation at these sites transforms Tau into an inhibitory molecule that dissociates microtubule-binding proteins from normal microtubules. In this application, the term "neuronal loss" generally refers to a reduction or weakening of the number or function of neurons in an organism. Neuron loss may manifest as the death of neurons. In this application, the term "Tau protein" generally refers to Tau (microtubule-associated protein tau, MAPT), a microtubule-stabilizing protein. Tau protein is abundant in neurons of the central nervous system, less common elsewhere, but also expressed at very low levels in astrocytes and oligodendrocytes of the central nervous system. Tau protein can control microtubule stability in two ways: through different subtypes and different phosphorylation levels. For example, the NCBI registry ID for human Tau subtype 1 is NP_058519.3. Alzheimer's disease (AD) may be associated with Tau protein, which is defective and unable to properly stabilize microtubules. In this application, the term "Neu-N" generally refers to Fox-3, Rbfox3, or hexanucleotide-binding protein-3, a neuronal nuclear antigen commonly used as a biomarker for neurons. In some embodiments, the vast majority of neurons may show strong Neu-N positivity, and Neu-N immunoreactivity can be widely used for neuron identification in tissue cultures and sections, as well as for measuring the neuron / glial cell ratio in brain regions. In this application, the term "necrosome" generally refers to programmed necrosis or inflammatory cell death. For example, necrosis may be associated with non-programmed cell death caused by cell damage, rather than orderly programmed cell death through apoptosis. In this application, the term "morphological change" generally refers to changes in the morphological structure and specific structural features of an organism. For example, morphological changes can include changes in external morphology (e.g., shape, structure, color, pattern, size) and / or internal morphology (e.g., the shape and structure of internal components). In this application, the term "hippocampus" generally refers to the major component of the brain located in the medial temporal lobe. In Alzheimer's disease, the hippocampus is likely one of the earliest areas of the brain to be damaged; short-term memory loss and disorientation are among the early symptoms. In this application, the term "Alzheimer's disease (AD)" generally refers to Alzheimer's disease, a chronic neurodegenerative disease that typically begins slowly and gradually worsens over time. For example, eight intellectual domains are most commonly impaired in Alzheimer's disease (AD): memory, language, perceptual skills, attention, motor skills, orientation, problem-solving, and executive function. These domains correspond to the NINCDS-ADRDA Alzheimer's disease criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association. In this application, the term "cognitive impairment" generally refers to cognitive impairment in patients with Alzheimer's disease (AD). For example, cognitive impairment may include impairment of learning function, memory function, cognitive function, sensory function, motor function, and / or emotional function. In this application, the term "apoptosis" generally refers to a genetically directed process of cellular self-destruction marked by nuclear DNA fragmentation, which can be activated by the presence or removal of an inhibitor or stimulant. Apoptosis is also known as cell suicide or programmed cell death. Bcl-2 family proteins are among the major intracellular regulators of apoptosis. Intracellular proteins of the Bcl-2 family help regulate the activation of proproteases. Some members of the Bcl-2 family promote prozymogen activation and cell death. For example, the apoptosis promoter Bad acts by binding to and inactivating death-inhibiting members of the family, while others such as Bax and Bak stimulate the release of cytochrome c from mitochondria. Bax and Bak themselves are also activated by other pro-apoptotic members of the Bcl-2 family, such as Bid. Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. The sequential activation of caspases plays an important role in the execution phase of apoptosis. Caspases exist as inactive prozymes. Through proteolytic hydrolysis at conserved aspartic acid residues, they produce two subunits, one large and one small, which dimerize to form an active enzyme. Caspase-3 is the main caspase involved in the cleavage of amyloid β4A precursor protein (APP), and is associated with neuronal death in Alzheimer's disease. Elevated levels of caspase 3 precursor ("Pro-caspase 3") and its cleaved form ("Cl-caspase 3") are generally associated with increased apoptosis. In this application, the term "necrosis" generally refers to a form of cell damage that leads to premature cell death in living tissue through autolysis. Signaling pathways are generally considered responsible for executing necrosis, or programmed necrosis. Viral infection produces TNFα, which stimulates its receptor TNFR1. The TNFR-associated death protein TRADD signals RIPK1 (receptor-interactive protein kinase 1), which recruits RIPK3 to form necrosomes. Phosphorylation of MLKL (mixed lineage kinase domain-like) by the riboptosome ("pMLKL") drives MLKL oligomerization, allowing MLKL to insert into and permeate the plasma membrane and organelles. MLKL integration leads to the release of inflammatory phenotypes and damage-associated molecular patterns (DAMPs), thereby triggering an immune response. Specifically, programmed necrosis is an ordered form of necrosis triggered by RIPK1 and RIPK3 MLKL... The study found that programmed necrosis is activated in the brains of Alzheimer's disease (AD) patients after death, showing a positive correlation with Braak stage of brain tissue and a negative correlation with brain weight and cognitive scores. Furthermore, the study also found significant overlap between genes regulated by RIPK1 and multiple independent Alzheimer's disease (AD) transcriptome features, indicating that RIPK1 activity is an important component that can explain the transcriptome changes in Alzheimer's disease (AD). In this application, the term "gliosis" generally refers to the fibrous proliferation of glial cells in areas of central nervous system (CNS) damage. Astroma is prevalent in gliomas and many other neurological diseases (such as Alzheimer's disease), as evidenced by elevated levels of glial fibrillary acidic protein (GFAP) in post-mortem tissue samples detected by immunohistochemistry. Normally, gliosis is a comorbidity of astrocytosis and microglia. In this application, the term "synaptic degeneration" generally refers to the loss or dysfunction of a synapse, which can be reflected by the state / expression of synaptic markers and / or postsynaptic density. Postsynaptic density (PSD) is a dense protein attached to the postsynaptic membrane. PSD was initially identified by electron microscopy as an electron-dense region on the postsynaptic neuronal membrane. The PSD is closely associated with the presynaptic active area and ensures proximity of receptors to presynaptic neurotransmitter release sites. For example, cavitation or swelling in the PSD may indicate synaptic degeneration. Synaptic state can be detected by detecting the expression or level of synaptophysin, a membrane glycoprotein present in various active neurons and also found upon neuronal stimulation. In this application, the term "donor nucleic acid molecule" generally refers to a nucleic acid molecule that provides a heterologous nucleic acid sequence to a recipient (e.g., a receiving nucleic acid molecule). In this application, the term "upstream" when used with DNA, RNA, or gene sequences generally refers to a relative position in a DNA, RNA, or gene sequence toward the 5' end. When considering double-stranded DNA, upstream refers to the 5' end of the coding strand of that gene. In this application, the term "downstream" when used with DNA, RNA, or gene sequences generally refers to a position in the DNA, RNA, or gene sequence facing the 3' end. When considering double-stranded DNA, downstream refers to the 3' end of the coding strand of that gene. In this application, the terms “hybridization” or “hybridization” as used in molecular biology generally refer to the process by which single-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules anneal to complementary DNA or RNA. In this application, the terms "induced pluripotent stem cells" or "iPS cells" generally refer to cells extracted from any tissue (typically skin or blood) of a child or adult and genetically modified to resemble embryonic stem cells. As the name suggests, these cells are pluripotent, meaning they are capable of forming most (if not all) adult cell types. In this application, the term "tracrRNA" generally refers to trans-activated crRNA (tracrRNA), which is a small trans-coding RNA. TracrRNA is complementary to and base-pairs with precrRNA to form an RNA double strand. It is activated by RNA-specific nuclear... Glyconuclease III cleaves the RNA, forming a crRNA / tracrRNA hybrid. This hybrid acts as a guide for the endonuclease Cas9, which cleaves the invading nucleic acid. In this application, the term "DDIT4L" generally refers to DNA damage-inducible transcript 4-like. It can also be referred to as REDD2 / RTP801L. The human DDIT4L gene has a GenBank accession number of 115265; the human DDIT4L protein has a GenBank accession number of NP_660287.1. In this application, the term "DDIT4L" includes human DDIT4L, its variants, isotypes and / or species homologues, and analogs that share at least one common epitope with said human DDIT4L. In this application, the terms "QDLIR" and "DIR" are used interchangeably and generally refer to the intron-retained cleavage product of DDIT4L. In this application, the amino acid sequence of the DIR may be as shown in SEQ ID NO:1. In this application, the term "DIR" includes human DIR, its variants, isotypes and / or species homologues, and analogs having at least one common epitope with said human DIR. In this application, the term "expression level" generally refers to the protein, RNA, or mRNA level of a specific related gene. The expression level of a specific related gene (e.g., the human DIR gene) can be determined using any method known in the art. In this application, "expression" generally refers to the process of transforming gene-encoded information into a structure present in and operating within the cell. This can include, for example, reverse transcription and amplification analysis (e.g., PCR, ligation RT-PCR, or quantitative RT-PCT), hybridization analysis, Northern blotting, dot blot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, or mass spectrometry. Analysis can be performed directly on biological samples or on proteins / nucleic acids isolated from samples. In this application, the term "neurodegenerative disease" generally refers to a neurological disease or condition resulting from the gradual loss of neuronal structure and function, including neuronal death and glial cell homeostasis. In some cases, age or gene mutations affecting CNS cell function can cause said neurodegenerative disease. The neurodegenerative disease may have changes and / or symptoms selected from: protein misfolding and aggregation; neuroinflammation; alterations in cell signal transduction; acquired aging / cell death (e.g., disrupted apoptotic signal transduction, mitochondrial dysfunction, impaired autophagy, and activation of necrosomes by stress / inflammation); motor cell damage; and epigenetic changes, etc. In this application, the term "early-onset dementia" can include early-stage, mid-stage, and / or late-stage dementia. For example, patients with early-stage dementia will experience increasingly pronounced learning and memory impairments, and in some cases, may have language impairments, executive function impairments, cognitive impairments (agnosia), and / or skill performance impairments (apraxia). For example, patients with mid-stage dementia will lose the ability to live independently and may be unable to perform most daily activities (in some cases, may suffer from agnosia, speech disorder, and / or loss of sensation). For example, patients with late-stage dementia may become dependent on caregivers. For example, they may completely lose their language abilities. For example, they may be unable to perform activities independently. Food. In this application, the term "cognitive impairment" generally refers to a progressive loss (including neuronal death) of neuronal structure and / or function that is believed to be involved or actually involves, or is related to, diseases and conditions. For example, the characteristics of said cognitive impairment may include impairment of cognition (e.g., memory, attention, perception, and / or thinking). These impairments may include pathogen-induced cognitive dysfunction, such as HIV-related cognitive dysfunction and Lyme disease-related cognitive dysfunction. In this application, the term "early cognitive impairment (MCI)" generally refers to a clinical state intermediate between normal cognition and cognitive impairment. In some cases, MCI may include cognitive impairment that meets the criteria for dementia but exceeds the degree of normal aging. MCI varies in clinical presentation, etiology, prognosis, and prevalence. In some cases, MCI may be a pathological stage of Alzheimer's disease. Certain forms of cognitive impairment can be seen as early manifestations of neurodegenerative diseases that will eventually lead to dementia. In some cases, MCI may include subtypes selected from the following group: aMCI-s: amnestic MCI with single cognitive domain impairment; aMCI-m: amnestic MCI with multi-cognitive domain impairment; naMCI-s: non-amnestic MCI with single cognitive domain impairment; and naMCI-m: non-amnestic MCI with multi-cognitive domain impairment. In this application, the term "cognitive impairment due to normal aging" generally refers to cognitive impairment caused by normal aging. For example, cognitive impairment due to normal aging may manifest as: memory loss, confusion about the location of familiar places, needing more time than usual to complete daily tasks, or changes in mood and personality. In this application, the term "aging stage" generally refers to the aging stage of a subject. For example, for humans, the aging stage can be 60 years or older, 70 years or older, or 75 years or older; for mice, the aging stage can be 10 months or older, for example, 13 months or older or 18 months or older. In some cases, subjects in the aging stage may have one or more symptoms of learning deficits, memory impairment, memory deficits, and / or brain dysfunction. In this application, the term "variant" generally refers to a polypeptide containing an amino acid sequence that differs from the amino acid sequence of a parent or reference polypeptide (e.g., a wild-type polypeptide) by at least one amino acid residue. In this application, the variant may have a high (e.g., at least 80%) homology with the parent or reference polypeptide. This homology may include sequence similarity or identity. In this application, homology can be determined using standard techniques known in the art (see, for example, Smith and Waterman, Adv. Appl. Math.); the percentage of identity shared by polynucleotide or polypeptide sequences is determined by direct comparison of sequence information between molecules, which is performed by sequence alignment and determination of identity using methods known in the art. An example of an algorithm suitable for determining sequence similarity is the BLAST algorithm (see Altschul et al., J. Mol. Biol. Journal of Molecular Biology, 215:403-410).

[1990] The software used for BLAST analysis is publicly available from the National Center for Biotechnology Information (NCBI). In this application, the term "about" generally refers to a numerical range that is 20% more or less than a specific value. For example, "about X" includes a numerical range of ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a number. value. In this application, the term "neuron" generally refers to a nerve cell, which is the primary functional unit of the nervous system. A neuron may consist of a cell body, its processes (axons), and one or more dendrites. Neurons can transmit information to other neurons or cells by releasing neurotransmitters at synapses. In this application, the term "cognitive ability" generally refers to the mental behavior of acquiring knowledge and understanding through thought, experience, and sensation. The concept of cognition may not be limited to mental concepts / domains, but may include, for example, executive functions, memory, perception, attention, emotion, motor control, and / or interference processing. On the one hand, this application provides a non-human animal or a portion thereof, which contains and / or expresses the intron-retained cleavage product DIR and / or its functionally active fragments of DNA damage-inducing transcript 4-like transcript (DDIT4L). On the other hand, this application provides a descendant or a portion thereof of the non-human animal described in this application, which is obtained by hybridizing the non-human animal of this application with another non-human animal, wherein the other non-human animal may or may not express the DIR and / or its functionally active fragments. For example, the other non-human animal may express and / or contain other genes or variants thereof associated with neurological diseases or conditions (e.g., APP, Tau, etc.). On the other hand, this application provides an isolated cell containing and / or expressing the intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or its functionally active fragments. On the other hand, this application provides an organization comprising and / or expressing the intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or its functionally active fragments. On the other hand, this application provides a cell line or cell culture. The cell line or cell culture is derived from the non-human animal or part thereof described in this application, its offspring, the cells described in this application, and / or the tissues described in this application. On the other hand, this application provides a composition. This composition may comprise the non-human animal or a portion thereof described in this application, its offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application. On the other hand, this application provides a kit. The kit may comprise: the non-human animal or part thereof described in this application, the progeny described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application; and one or more additional components selected from the group consisting of: analytical buffers, controls, substrates, standards, detection materials, laboratory supplies, equipment, instruments, cells, organs, tissues, and a user manual or instruction manual. On the other hand, this application provides a method for screening and / or identifying substances, devices, and / or compositions for treating, preventing, and / or prognosing neurological diseases or conditions. The method may include: applying candidate substances, devices, and / or compositions to non-human animals or portions thereof described in this application, progeny described in this application, cells described in this application, tissues described in this application, and / or cell lines or primary cell cultures described in this application; and determining the candidate substances, devices, and / or combinations. The effect of the substance on one or more indicators of the aforementioned neurological disease or condition. On the other hand, this application provides a method for designing substances, devices, and / or compositions for treating, preventing, and / or prognosing neurological diseases or conditions, the method comprising: (i) applying candidate substances, devices, and / or compositions to a non-human animal or part thereof described in this application, a progeny described in this application, a cell described in this application, a tissue described in this application, and / or a cell line or primary cell culture described in this application; (ii) determining the effect of the candidate substances, devices, and / or compositions on one or more indications of the neurological disease or condition; (iii) selecting candidate substances, devices, and / or compositions capable of preventing, inhibiting, and / or alleviating one or more of the indications of the neurological disease or condition; and (iv) modifying the structure and / or composition of the candidate substances, devices, and / or compositions of step (iii) to obtain modified substances, devices, and / or compositions having improved activity in treating, preventing, and / or prognosing the neurological disease or condition. On the other hand, this application provides a method for identifying potential biological targets and / or biomarkers that can be used to treat, prevent, and / or prognose neurological diseases or conditions, the method comprising: (i) performing quantitative or qualitative proteomics, lipidomics, and / or genomics comparative analysis on the non-human animal or part thereof described in this application, the offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application with corresponding controls; (ii) identifying genes, proteins, and / or lipids with altered sequences, contents, expression levels, modifications, and / or activities; (iii) wherein the genes, proteins, and / or lipids identified in step (ii) are potential biological targets and / or biomarkers that can be used to treat, prevent, and / or prognose the neurological diseases or conditions. On the other hand, this application provides a method for screening biological targets and / or biomarkers for diagnosing and / or monitoring neurological diseases or conditions, the method comprising: determining the presence and / or levels of substances in samples obtained from non-human animals or parts thereof, progeny thereof, cells thereof, tissues thereof, and / or cell lines or primary cell cultures thereof, respectively, before and after the occurrence of one or more relevant indicators of the neurological disease or condition, to identify substances whose presence and / or levels change before and after the occurrence of the indicators, and identifying such substances as the biological targets and / or the biomarkers. On the other hand, this application provides the use of the non-human animals or portions thereof described in this application, their offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application in the preparation of identification and / or screening systems. These systems can be used to identify and / or screen substances, devices, compositions, biological targets, and / or biomarkers for the treatment, diagnosis, prevention, monitoring, and / or prediction of neurological diseases or conditions. The non-human animals or parts thereof described in this application, their offspring, cells, tissues, and / or cell lines or primary cell cultures described in this application may be used to screen substances, devices, compositions, biological targets, and / or biomarkers for the treatment, diagnosis, prevention, monitoring, and / or prediction of neurological diseases or conditions. On the other hand, this application provides a method for preparing the non-human animal or a portion thereof, the cell or tissue described in this application, the method comprising causing the non-human animal or a portion thereof, the cell or tissue to contain and / or express the DIR and / or its functionally active fragments. On the other hand, this application provides a method for preparing a disease model, the method comprising causing a non-human animal or a part thereof, cell or tissue to contain and / or express DIR and / or its functionally active fragments. Non-human animals, their offspring, or parts thereof In any aspect of this application, the non-human animal may be a gene-edited non-human animal, or a non-human animal derived from a gene-edited non-human animal. For example, the non-human animal may be a gene-knock-in non-human animal, or a non-human animal derived from a gene-knock-in non-human animal. For example, the non-human animal can be a non-human mammal. In some embodiments, the non-human animal is a rodent or a primate. In some embodiments, the non-human animal is selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats. For example, the mouse can be of the C57 / B6 strain. In any aspect of this application, a portion of the non-human animal or its offspring may include its organs, tissues, and / or cells. In some embodiments, the portion includes bodily fluids. For example, the bodily fluids may be selected from the group consisting of blood, plasma, serum, urine, sweat, tears, saliva, semen, and cerebrospinal fluid. In some embodiments, the plasma includes exosomes. In some embodiments, the portion includes the brain (e.g., brain tissue) or a portion thereof. The portion of the brain may include parts selected from the group consisting of the olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, and cerebellum. In some embodiments, the portion includes the olfactory mucosa. In some embodiments, the portion includes a portion of the central nervous system, a portion of the peripheral nervous system, skin tissue, muscle tissue, and / or visceral organs. For example, the central nervous system may include the spinal cord. In some embodiments, the portion includes cells. The cells may include cells selected from the group consisting of: primary neurons, microglia, astrocytes, oligodendrocytes, macrophages, perivascular epithelial-like cells, B cells, T cells, adult stem cells, NK cells, pluripotent stem cells, unipotent stem cells, embryonic stem cells, induced pluripotent stem cells, and gametes. For example, the gametes may include sperm and / or oocytes. In some implementations, the portion (e.g., the organ, tissue, or cell) cannot develop into a complete non-human animal. In some embodiments, the non-human animal, its offspring, or portions thereof contains the DIR and / or its functionally active fragments. For example, the DIR and / or its functionally active fragments may be expressed by the animal, its offspring, or the cell, or may be derived from other sources and then introduced (e.g., injected into) the animal, its offspring, or the cell to contain the DIR and / or its functionally active fragments. In some embodiments, the non-human animal, its offspring, or parts thereof express the DIR and / or its functionally active fragments. In certain circumstances, the expressed DIR and / or its functionally active fragments may be secreted or otherwise expelled from the cells, tissues, or animal body. The expression of DIR may include the expression of the DIR gene, the expression of the transcript of the DIR gene, and / or the expression of the DIR protein. For example, the expression may include the expression of a specific gene (e.g., the human DIR gene) polynucleotide, mRNA, or amino acid product or protein. The expression may include the expression of fragments of polynucleotides transcribed from a specific gene (e.g., the human DIR gene), translated proteins, or post-translational modified proteins. The expression of the functionally active fragment of the DIR (e.g., DIR-IR, DIR-I, and / or DIR-II) may include the expression of a gene encoding the functionally active fragment of the DIR, a transcript of the gene encoding the functionally active fragment of the DIR, and / or the expression of a protein encoding the functionally active fragment of the DIR. For example, the expression may include the expression of a polynucleotide, mRNA, or amino acid product or protein of a specific gene (e.g., a gene encoding a functionally active fragment of the human DIR, such as DIR-IR, DIR-I, and / or DIR-II). The expression may include the expression of a fragment of a polynucleotide transcribed from a specific gene (e.g., a gene encoding a functionally active fragment of the human DIR, such as DIR-IR, DIR-I, and / or DIR-II), a translated protein, or a post-translational modified protein. For example, the amino acid sequence of DIR-IR may be as shown in SEQ ID NO:2. For example, the amino acid sequence of DIR-I may be as shown in SEQ ID NO:4. For example, the amino acid sequence of DIR-II may be as shown in SEQ ID NO:5. In this application, the expression or content of DIR can be identified by using substances selected from the group consisting of: primers that specifically amplify the DIR gene, nucleic acid molecules that specifically bind to the DIR gene, nucleic acid molecules that specifically bind to the DIR protein, small molecules that specifically bind to the DIR protein, probes that specifically bind to the DIR protein, and polypeptides that specifically bind to the DIR protein. In this application, the content or expression of the functionally active fragments of DIR (e.g., DIR-IR, DIR-I, and / or DIR-II) can be identified using substances selected from the group consisting of: primers that specifically amplify the functionally active fragment gene of DIR, nucleic acid molecules that specifically bind to the functionally active fragment gene of DIR, nucleic acid molecules that specifically bind to the functionally active fragment of DIR (e.g., DIR-IR, DIR-I, and / or DIR-II), small molecules that specifically bind to the functionally active fragments of DIR (e.g., DIR-IR, DIR-I, and / or DIR-II), probes that specifically bind to the functionally active fragments of DIR (e.g., DIR-IR, DIR-I, and / or DIR-II), and polypeptides that specifically bind to the functionally active fragments of DIR (e.g., DIR-IR, DIR-I, and / or DIR-II). In this application, the expression and / or content of the DIR and / or its functionally active fragments can be determined by performing an assay selected from the group consisting of: reverse transcription and amplification analysis (e.g., PCR, ligation RT-PCR, or quantitative RT-PCT), hybridization analysis, Northern blotting, dot blot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, or mass spectrometry. For example, it can be determined by qPCR, qRT-PCR, or Northern blotting. Hybridization, Western blot hybridization, and / or ELISA assays can be used to measure the expression or content of the DIR described in this application. The expression and / or content of the DIR can also be measured by performing analysis directly on biological samples or on proteins / nucleic acids isolated from samples. In some cases, non-human animals can be made to express and / or contain the DIR and / or its functionally active fragments by placing them under specific conditions or environments (e.g., stress or hypoxia). DIR and / or its functionally active fragments This is an intron-retained form (DIR) produced by abnormal splicing of human DDIT4L. Sequence alignment revealed that this nucleic acid sequence is conserved in primates, with high conservation in chimpanzees (closely related to humans) and relatively poor conservation in macaques. However, it shows low conservation in commonly used laboratory animals such as rats, mice, dogs, and pigs. In any aspect of this application, the DIR may be derived from mammals, such as primates, for example, humans. For example, the DIR or its functionally active fragment may comprise the amino acid sequence encoded by the intron retained in DDIT4L. In some embodiments, the DIR or its functionally active fragment comprises the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5, or a functional variant or truncated form thereof. The functional variant may comprise substitutions, deletions, or additions of one or more amino acids (e.g., one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more). In some embodiments, the gene encoding the DIR and / or its functionally active fragment is homozygous. In some embodiments, the gene encoding the DIR and / or its functionally active fragment is heterozygous. In some embodiments, the expression of the DIR and / or its functionally active fragment is regulated by a corresponding endogenous regulatory element in the genome of the non-human animal or cell. For example, the expression of the DIR and / or its functionally active fragment may be regulated by a regulatory element (e.g., a promoter and / or enhancer element) of the DDIT4L encoding gene in the genome of the non-human animal or cell. For example, the gene encoding the DIR and / or its functionally active fragment may comprise the nucleic acid sequence shown in any one of SEQ ID NO:12-15, or a functional variant or truncated version thereof. The functional variant may comprise one or more (e.g., one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more) nucleotide substitutions, deletions, or additions. In this application, the functionally active fragment generally refers to a polypeptide containing an amino acid sequence that differs from the parent or reference polypeptide (e.g., the full-length amino acid sequence of human DIR) by at least one amino acid residue. In this application, the functionally active fragment may have a high (e.g., at least 80%) homology with the parent or reference polypeptide. The homology may include sequence similarity or identity. In this application, the homology may be determined using standard techniques known in the art (see, for example, Smith and Waterman, Adv. Appl. Math. Advances in Applied Mathematics); the percentage of identity shared by polynucleotide or polypeptide sequences is determined by direct comparison of sequence information between molecules, which is performed by sequence alignment and determination of identity using methods known in the art. An example of an algorithm suitable for determining sequence similarity is the BLAST algorithm (see Altschul et al., J. Mol. Biol. Journal of Molecular Biology, 215:403-410

[1990] ). Software for performing BLAST analysis is publicly available from the National Center for Biotechnology Information (NCBI). The functionally active fragment of the DIR may have at least one activity equivalent to or related to the DIR. For example, the activity of the DIR and / or its functionally active fragment may include the biological activity of the DIR protein. For example, the biological activity may include influencing the excitability of neurons and / or inhibiting neuronal activity. For example, the biological activity may include inhibiting cognitive abilities by inhibiting neuronal excitability and / or inhibiting neuronal activity. In some cases, the biological activity may include the ability to reduce the frequency of excitatory postsynaptic currents (EPSCs) and / or the ability to reduce the amplitude of EPSCs. For example, the reduction may include, compared to the biological activity of the original DIR and / or its functionally active fragment in the subject, administration of the DIR and / or its functionally active fragment and / or nucleic acids encoding the DIR and / or its functionally active fragment, reducing the frequency of excitatory postsynaptic currents (EPSCs) in the subject and / or reducing the amplitude of EPSCs in the subject. For example, the functionally active fragment of the DIR (e.g., DIR-IR, DIR-I, or DIR-II) can reduce the frequency of EPSCs. For example, the reduction can include a decrease in the frequency of EPSCs by at least about 10% after administration of the functionally active fragment of the DIR compared to the original frequency of EPSCs in the subject. For example, the reduction can be at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500%, or more. In this application, the biological activity may include influencing cognitive abilities. Specifically, the biological activity may include involvement in signaling pathways related to Aβ accumulation and / or involvement in signaling pathways related to Tau tangles formation. For example, the DIR and / or its functionally active fragments may inhibit cognitive abilities. For instance, the DIR and / or its functionally active fragments may inhibit cognitive abilities by suppressing signaling pathways related to Aβ accumulation and / or suppressing signaling pathways related to Tau tangles formation. Cells, tissues, cell lines and cell cultures In this application, the cells may be non-human animal cells. In this application, the tissues may be non-human animal tissues. For example, the non-human animal can be a non-human mammal. For example, the non-human animal can be selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats. In some cases, the non-human animal can be a rodent or a primate. The cells described in this application may include cells selected from the group consisting of: neuroblastoma cells, glioma cells, primary neurons, microglia, astrocytes, oligodendrocytes, macrophages, perivascular epithelial-like cells, B cells, T cells, adult stem cells, NK cells, pluripotent stem cells, unipotent stem cells, embryonic stem cells, and induced pluripotent stem cells. Cells and gametes. For example, the gametes may include sperm and / or oocytes. The tissue described in this application may include bodily fluids. For example, the bodily fluids may be selected from the group consisting of blood, plasma, serum, urine, sweat, tears, saliva, semen, and cerebrospinal fluid. For example, the plasma may contain exosomes. The tissue may include the brain or a portion thereof. A portion of the brain may include parts selected from the group consisting of the olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, and cerebellum. For example, the tissue may include the olfactory mucosa. According to any aspect of this application, the tissue may include a portion of the central nervous system, a portion of the peripheral nervous system, skin tissue, muscle tissue, and / or visceral organs. For example, the central nervous system may include the spinal cord. In some embodiments, the cell or tissue cannot develop into a complete non-human animal. For example, the cell may not be a pluripotent stem cell or an embryonic stem cell. In this application, the cell may be a gene-edited cell or a cell derived from a gene-edited cell. For example, the cell may be a gene knock-in cell or a cell derived from a gene knock-in. For example, the expression of the DIR and / or its functionally active fragments may be regulated by corresponding endogenous regulatory elements in the cell's genome. In this application, the tissue may be a gene-edited tissue (e.g., at least some of the cells in the tissue may be gene-edited cells), or derived from a gene-edited tissue (e.g., differentiated or cultured from a gene-edited tissue). For example, the tissue may be a gene knock-in tissue (e.g., at least some of the cells in the tissue may be gene knock-in cells), or derived from a gene knock-in tissue (e.g., differentiated or cultured from a gene knock-in tissue). For example, the expression of the DIR and / or its functionally active fragments may be regulated by corresponding endogenous regulatory elements in the tissue genome. The cell line or cell culture of this application can be a primary cell culture. For example, the cell line may be derived from the cells, tissues, or non-human animals or parts thereof described in this application. For example, the cell culture can be an in vitro culture, such as a culture in a two-dimensional culture system or a culture in a three-dimensional culture system. For example, the cell culture can be an organoid. Compositions and kits The compositions of this application may comprise the non-human animal or part thereof described in this application, the progeny described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cell cultures described in this application. Furthermore, the compositions may also comprise one or more other adjuvants or excipients, such as pharmaceutically acceptable buffer solutions, other reagents, excipients, etc. This application also provides a kit. The kit may contain: the non-human animal or a portion thereof described in this application, the offspring described in this application, the cells described in this application, the tissues described in this application, and / or the cell lines or primary cells described in this application. Cultures; and one or more additional components selected from the group consisting of: analytical buffers, controls, substrates, standards, assay materials, laboratory supplies, equipment, instruments, cells, organs, tissues, and user manuals or instructions. For example, the user manual or instruction manual may describe the screening, detection, or identification methods described in this application. The buffer solution can be used to analyze the performance of the non-human animal, its parts, the tissue, cell, cell line, or cell culture. The control can be used as a reference for the non-human animal, tissue, cell, cell line, cell culture, etc., of this application to detect or evaluate the properties or activities of the non-human animal, tissue, cell, cell line, cell culture, etc. Similarly, the substrates, standards, testing materials, laboratory supplies, equipment, instruments, etc., may also be used in conjunction with or in combination with the non-human animals, parts thereof, tissues, cells, cell lines or cell cultures of this application for analysis, screening or determination. In addition, the composition or kit may include other cells, organs or tissues that can be co-cultured or used with non-human animals, parts thereof, tissues, cells, cell lines or cell cultures of the present application. In the compositions or kits of this application, the non-human animals, their parts, tissues, cells, cell lines, and / or cell cultures described in this application may be mixed together with the other components, or they may be placed in their respective independent containers without being mixed with each other. Preparation method This application also provides a method for preparing the non-human animal or a portion thereof, the cell or tissue described in this application, the method comprising causing the non-human animal or a portion thereof, the cell or tissue to contain and / or express the DIR and / or its functionally active fragments. On the other hand, this application also provides a method for preparing a disease model, the method comprising causing a non-human animal or a part thereof, cell or tissue to contain and / or express DIR and / or its functionally active fragments. For example, the method may include introducing the DIR, its functionally active fragment, nucleic acid molecule encoding the DIR, and / or nucleic acid molecule encoding a functionally active fragment of the DIR into the non-human animal or a part thereof, the cell, tissue, cell line, and / or cell culture. The introduction may include, for example, injection into the non-human animal, its part, the tissue, or the cell (e.g., injection of a protein or nucleic acid molecule). The introduction may also include, for example, other means of introducing exogenous proteins, exogenous nucleic acid molecules, etc., into cells, tissues, or animals, such as nucleic acid molecule transfection or viral transduction. In some embodiments, the method may include knocking in a nucleic acid sequence encoding the DIR and / or a functionally active fragment thereof into the non-human animal or a portion thereof, the cell, tissue, cell line and / or cell culture. In the preparation method described in this application, nucleases can be used to assist in the modification of target gene sites. Such nucleases can promote homologous recombination between donor nucleic acid molecules and target gene sites. In some embodiments, the nuclease includes a nuclease... Acid endonuclease. In this application, the term "recognition site of a nuclease" generally refers to a DNA sequence on which a nuclease can cause a nick or double-strand break. The recognition site of a nuclease can be endogenous (or natural) or exogenous. In some embodiments, the recognition site can be exogenous and therefore not naturally present in the cell's genome. In other embodiments, the exogenous or endogenous recognition site may be present only once in the host cell's genome. In specific embodiments, endogenous or natural sites that occur only once within the genome can be identified, and such sites can then be used to design nucleases that will produce a nick or double-strand break at the endogenous recognition site. The length of the recognition site can vary, including, for example, recognition sites with a length of at least 4, 6, 8, 10, 12, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or more nucleotides. In some embodiments, each monomer of the nuclease can recognize a recognition site of at least 9 nucleotides. In other embodiments, the recognition site can be about 9 to 12 nucleotides long, about 12 to 15 nucleotides long, about 15 to 18 nucleotides long, or about 18 to 21 nucleotides long, as well as any combination of these subranges (e.g., 9–18 nucleotides). The recognition site can be a palindrome, meaning that the sequence on one strand is identical to the sequence on the complementary strand in the opposite direction. A specific nuclease can bind to and cleave the recognition site, or the nuclease can bind to a sequence different from the recognition site. Furthermore, the term "recognition site" can encompass both a nuclease binding site and a cleavage / cutting site, regardless of whether the cleavage / cutting site is inside or outside the nuclease binding site. In some cases, nuclease cleavage can occur at opposite nucleotide positions to produce a blunt-end cut, or in other cases, the cuts can be staggered to produce a single-stranded overhang, also known as a "sticky end," which can be a 5' overhang or a 3' overhang. Any nuclease that produces a nick or double-strand break at the desired recognition site can be used in the methods of this application. Naturally occurring or native nucleases can be used, provided that the nuclease induces a nick or double-strand break at the desired recognition site. Alternatively, modified or engineered nucleases can be used; "engineered nucleases" include nucleases engineered (modified or derived) from their natural form to specifically recognize and produce a nick or double-strand break at the desired recognition site. Therefore, engineered nucleases can be derived from natural or naturally occurring nucleases, or they can be artificially produced or synthesized. Modification of the nuclease can be as simple as a change of one amino acid or one nucleotide. In some embodiments, the engineered nuclease may contain a nick or double-strand break at the recognition site, wherein the recognition site is not a sequence that a natural (non-engineered or unmodified) nuclease can recognize. In this document, producing a nick or double-strand break at the recognition site or other DNA may be referred to as "cutting" or "shearing" the recognition site or the DNA. In some implementations, the nuclease may be a transcription activator-like effector nuclease. Activator-Like Effector Nucleases (TALENs) are a class of sequence-specific nucleases that can be used to generate double-strand breaks at specific target sequences in the genomes of prokaryotes or eukaryotes. TAL effector nucleases can be generated by fusing natural or engineered transcription activator-like (TAL) effectors or their functional portions into the catalytic domain of a nuclease (e.g., FokI). Unique, modular TAL effector DNA-binding domains allow for the design of proteins with specific DNA recognition specificity. Therefore, the DNA-binding domains of TAL effector nucleases can be engineered to recognize specific DNA target sites and thus be used to generate double-strand breaks at desired target sequences. See WO 2010 / 079430; see WO 2010 / 079430; Morbitzer et al., (2010) PNAS 10.1073 / pnas.1013133107; Scholze & Boch (2010) Virulence 1: 428-432; Christian et al., (2010) Genetics 186: 757-761; Li et al., (2010) Nuc. Acids Res., doi: 10.1093 / nar / gkq704; Miller et al., (2011) Nature Biotechnology 29: 143-148; all of these are cited and incorporated herein by reference. In some embodiments, the nuclease may be a zinc-finger nuclease (ZFN). For example, each monomer of a ZFN may contain three or more zinc-finger-based DNA-binding domains, wherein each zinc-finger-based DNA-binding domain can bind a 3 bp subsite. In other embodiments, the ZFN may be a chimeric protein comprising a zinc-finger-based DNA-binding domain operably linked to a separate nuclease. In some embodiments, the separate endonuclease may be a FokI endonuclease. In some embodiments, the nuclease may comprise a first ZFN and a second ZFN, wherein each of the first and second ZFNs is operably linked to a FokI nuclease, wherein the first and second ZFNs recognize two consecutive target DNA sequences on each single strand of a target DNA sequence, the sequences being separated by a cleavage site of about 6 bp to about 40 bp or a cleavage site of about 5 bp to about 6 bp, and wherein the FokI nuclease dimers and produces a double-strand break. See also: US20060246567; US20080182332; US20020081614; US20030021776; WO / 2002 / 057308A2; US20130123484; US20100291048; and WO / 2011 / 017293A2, all of which are incorporated herein by reference. In some implementations, the nuclease can be a meganuclease. Based on conserved sequence motifs, meganucleases have been classified into four families. These different motifs are involved in the coordination of metal ions and the hydrolysis of phosphodiester bonds. HEases are known for their long recognition sites and tolerance to certain sequence polymorphisms in their DNA substrates. The domains, structures, and functions of meganucleases are known, see: e.g., Guhan and Muniyappa (2003) Rev Biochem Mol Biol 38: 199-248; Lucas et al. (2001) Nucleic Acids Res 29: 960-9; Jurica and Stoddard (1999) Cell Mol Life Sci 55: 1304-26; Stoddard (2006) Q Rev Biophys 38: 49-95; and Moure et al. (2002) Nat Struct Biol 9: 764. In some embodiments, the nuclease used in the methods of this application can be a CRISPR / Cas system. This system can use, for example, a Cas9 nuclease, and in some cases, the Cas9 nuclease can be targeted to the desired cell type expressing it. Codon optimization is performed. This system can be further utilized with a fused crRNA-tracrRNA vector that works in conjunction with a codon-optimized Cas9. This single RNA is often referred to as a small guide RNA or sgRNA. Within the sgRNA, the crRNA portion can be defined as a "nucleotide sequence that hybridizes to an endogenous target sequence" (or "target sequence"), and the tracrRNA is typically used as a "scaffold." In short, a short DNA fragment containing the target sequence is inserted into the sgRNA expression plasmid. The sgRNA expression plasmid may contain the target sequence (approximately 20 nucleotides in some embodiments), the tracrRNA sequence (scaffold), and a suitable promoter active in the cell and the necessary elements for proper functioning in eukaryotic cells (e.g., mouse cells). The sgRNA expression component and the Cas9 expression component can then be introduced into the cell. See, for example, Mali P et al., (2013) Science, 339(6121): 823-6; Jinek M et al., (2012) Science, 337(6096): 816-21; Hwang WY et al., (2013) Nat Biotechnol, 31(3): 227-9; Jiang W et al., (2013) Nat Biotechnol, 31(3): 233-9; and Cong L et al., (2013) Science, 339(6121): 819-23. All of these are incorporated herein by reference. For example, in the preparation method of this application, the knock-in may include: in the presence of a donor nucleic acid molecule containing the nucleic acid sequence, contacting the genome of the non-human animal, cell, or tissue with: 1) a CRISPR-associated (Cas) protein; and 2) one or more ribonucleic acid (RNA) sequences, the RNA comprising: i) a portion complementary to the target site and ii) a binding site of the Cas protein. For example, the binding site of the Cas protein may comprise a tracrRNA sequence. In some embodiments, the RNA sequence comprises the nucleic acid sequence shown in SEQ ID NO:6. In some cases, the knock-in also includes culturing the cells or tissues under conditions in which the one or more RNA sequences hybridize with the target sequence, and the Cas protein cleaving the target sequence after the hybridization with the RNA sequence. In the method of this application, the Cas protein may be provided in the form of a protein, a messenger RNA (mRNA) encoding the Cas protein, or DNA encoding the Cas protein. In the method of this application, the one or more RNA sequences may be provided in the form of one or more RNA molecules or one or more DNA molecules encoding the RNA sequence. The Cas protein may be a type I Cas protein; in some embodiments, the Cas protein may be a type II Cas protein; in some embodiments, the Cas protein may be Cas9. In some implementations, the method may further include identifying modified cells or non-human animals containing the knock-in heterologous nucleic acid sequence. Donor nucleic acid molecules containing heterologous nucleic acid sequences may also contain 5' and 3' homologous arms. The 5' and 3' homologous arms may be located flanking the heterologous nucleic acid sequence encoding the DIR and / or its functionally active fragment. Homologous arms (e.g., 5' or 3' homologous arms) in the donor nucleic acid molecule may have any length sufficient to promote homologous recombination with the corresponding region in the endogenous target site (e.g., endogenous DDIT4L), for example, at least 5 bp, at least 50 bp, at least 100 bp, at least 150 bp. At least 200 bp, at least 300 bp, at least 400 bp, at least 500 bp, at least 600 bp, at least 700 bp, at least 750 bp, at least 800 bp, at least 850 bp, at least 900 bp, at least 1 kb, at least 1.5 kb, at least 5 kb, or longer. In some implementations, the donor nucleic acid molecule includes a 5' homologous arm of approximately 800-900 bp and a 3' homologous arm of approximately 800-950 bp. In this application, the homologous arms and the target gene site (i.e., the homologous gene region or corresponding region within the endogenous DDIT4L gene site) match or correspond to each other. In this case, the mutual consistency of the two local sequences is sufficient as the basis for homologous recombination. "Homologousity" refers to the DNA sequence being identical to or having a certain degree of sequence consistency with the corresponding or matching sequence. The sequence consistency between a specific target site and the corresponding homologous arm found in the donor nucleic acid molecule can be any degree of sequence consistency that allows homologous recombination to occur. For example, the degree of sequence identity shared between the homologous arms of the donor nucleic acid molecule (or its fragment) and the target site (or its fragment) can be at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100%, in order to enable homologous recombination of the sequence. For example, in a donor nucleic acid molecule, the heterologous nucleic acid sequence encoding DIR and / or its functionally active fragment is flanked by: 1) a first homologous arm (or 5' homologous arm) corresponding to the endogenous DDIT4L gene; and 2) a second homologous arm (or 3' homologous arm) corresponding to the endogenous DDIT4L. Thus, through homologous recombination occurring between the homologous arms and their corresponding regions at the endogenous DDIT4L gene site, the heterologous nucleic acid sequence integrates into the endogenous DDIT4L gene site in a non-human animal or cellular genome. When using nucleases (e.g., Cas proteins), homologous genomic regions corresponding to the 5' and 3' homologous arms of the donor nucleic acid molecule are located sufficiently close to the nuclease target site to facilitate homologous recombination events between the homologous genomic regions and homologous arms in the event of a gap or double-strand break at the recognition site. For example, the nuclease target site can be located anywhere between the homologous genomic regions corresponding to the 5' and 3' homologous arms. In some embodiments, the recognition site is adjacent to at least one or both of the corresponding homologous genomic regions. The donor nucleic acid molecule may also contain a selection component or a reporter gene. The selection component may contain a nucleic acid sequence encoding a selection marker, wherein said nucleic acid sequence can be efficiently linked to a promoter. The promoter may be active in the target prokaryotic cells and / or in the target eukaryotic cells. Such promoters may be inducible promoters, endogenous promoters of reporter genes or cells, heterologous promoters of reporter genes or cells, cell-specific promoters, tissue-specific promoters, or developmental stage-specific promoters. In some embodiments, the selection marker may be selected from the group consisting of: ampicillin resistance gene (Ampr), neomycin phosphotransferase (Neor), hygromycin B phosphotransferase (Hygr), and puromycin-N-acetyltransferase (Puror). Rice blast-killing S-deaminase (Bsrr), xanthine / guanine phosphoribosyltransferase (Gpt), or herpes simplex virus thymidine kinase (HSV-k) or combinations thereof. The selection marker for the donor nucleic acid molecule can be located on either side of the 5' and 3' homologous arms, or at either the 5' or 3' position of the homologous arm. In some embodiments, the donor nucleic acid molecule may contain a reporter gene that can be efficiently linked to a promoter, wherein the reporter gene encodes a reporter protein selected from the following: LacZ, mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, enhanced yellow fluorescent protein (EYFP), Emerald, enhanced green fluorescent protein (EGFP), CyPet, cyan fluorescent protein (CFP), Cerulean, T-Sapphir, luciferase, alkaline phosphatase, and combinations thereof. Such a reporter gene can be efficiently linked to a promoter that is active in the cell. This promoter can be an inducible promoter, a reporter gene or an endogenous promoter, a reporter gene or a heterologous promoter, a cell-specific promoter, a tissue-specific promoter, or a developmental stage-specific promoter. In one or more RNA sequences, the complementary portion to the target gene and the binding site of the Cas protein (e.g., tracrRNA) can be contained in the same RNA molecule or in different RNA molecules. They can be introduced together as a single transcript or separately into non-human animals or cells. In some implementations, the Cas protein, the RNA portion complementary to the target gene, and the Cas protein binding site (e.g., tracrRNA) can be introduced as a protein-RNA complex into non-human animals or cells. In some implementations, the DNA encoding the Cas protein may be in the form of a first expression vector containing a first promoter that is effectively linked to the nucleic acid encoding the Cas protein. In some implementations, the DNA encoding an RNA portion complementary to the target gene may be in the form of a second expression vector containing a second promoter that is effectively linked to the nucleic acid encoding the RNA portion. In some implementations, the DNA encoding the Cas protein binding site (e.g., tracrRNA) may be in the form of a third expression vector containing a third promoter that is effectively linked to the nucleic acid encoding the Cas protein binding site (e.g., tracrRNA). The first, second, and third promoters can be active in the non-human animal or cell. In some implementations, the first, second, and third expression vectors may be contained in the same nucleic acid molecule. Screening / Identification / Design Methods In the screening, identification, or design methods of this application, one or more indicators of the neurological disease or condition include: expression and / or accumulation of Aβ; expression and / or accumulation of APP fragments; phosphorylation of Tau protein; oligomerization and / or aggregation of Tau protein; changes in brain morphology and / or brain weight; formation of neurofibrillary tangles; changes in learning function, memory function, cognitive function, sensory function, motor function, emotional function, and / or synaptic function; brain injury; neuronal loss, necrosome formation, neuronal death, changes in neuronal activity, neuronal apoptosis, neuronal necrosis, and programmed neuronal cell death. The number of Neu-N positive neurons and / or neurodegeneration; glial proliferation, microglia activation, astrocyte activation and / or inflammatory response; oxidative stress and / or mitochondrial dysfunction; vascular dysfunction; misfolded protein degradation and / or autophagy failure; and / or changes in brain glucose and / or lipid metabolism. For example, the accumulation of Aβ may include Aβ oligomerization and / or amyloid plaque formation. For example, the APP fragments may include sAPP, CTF-β, CTF-a, and / or AICD. For example, the synaptic function may include synaptic transmission, synaptic plasticity, synaptic protein formation and / or function, and / or synaptic morphology. For example, the inflammatory response may include a response via innate immune cells. For example, said innate immune cells may include T cells, B cells, NK cells, macrophages, and / or dendritic cells. For example, the vascular dysfunction may include amyloid angiopathy and / or blood-brain barrier (BBB) ​​damage. For example, the device may include a medical device, such as a medical device claimed to be effective in the treatment, diagnosis, prevention, monitoring, and / or prognosis of Alzheimer's disease. For example, the composition may comprise a mixture derived from one or more organisms. For example, the organisms may include plants, animals, and / or microorganisms. For example, the composition may comprise tissue homogenates and / or blood samples. In some embodiments, the composition may comprise extracts from one or more plants. For example, the composition may comprise candidate traditional Chinese medicines. The identification, screening, or design methods described in this application can be in vitro, ex vivo, or in vivo methods. In this application, the candidate substance may be a synthetic compound, peptide, protein, DNA library or nucleic acid molecule in such library, extract of animal (e.g., mammalian, such as mouse, rat, pig, cow, sheep, monkey or human) tissue or cell culture supernatant, extract or culture product of plant or microorganism, or any mixture of the above substances. In this method, after treating the non-human animal, its portion, its progeny, the tissue, cell, or cell line described in this application with the candidate substance, device, and / or composition, the tissue / cells are homogenized using a suitable buffer (e.g., phosphate buffer) to obtain a homogenate solution. Soluble and / or insoluble components can then be separated from the homogenate solution. Subsequently, detection can be performed by an immunoassay, for example, using anti-Aβ antibodies and / or anti-APP antibodies. In some embodiments, the amounts of Aβ42 and Aβ40 can be measured. In some embodiments, the Aβ42 / Aβ40 ratio can also be calculated. In some embodiments, after isolating the brain or brain tissue / cells, frozen sections or paraffin-embedded sections of the brain or brain tissue / cells can be prepared. APP or Aβ deposition can then be assessed, for example, by immunostaining the brain sections with anti-APP antibodies and / or anti-Aβ antibodies. Additionally, synaptic abnormalities can be assessed by immunostaining the brain with antibodies targeting presynaptic or dendritic marker proteins. Morphological abnormalities of cytoskeletal proteins can be assessed by immunostaining brain sections with antibodies against phosphorylated Tau protein. Neuronal cell death can be evaluated using Nissl staining or HE staining (e.g., as described in Am. J. Pathol, 2004, Vol. 165, pp. 1289-1300). Results can be compared with those of a control group (e.g., where no candidate substance, device, and / or composition was used, or where a blank control buffer was applied instead of the candidate substance, device, and / or composition). If, after administration of a candidate substance, device, and / or composition, the total amount of Aβ decreases, the amount of Aβ42 decreases, and / or the Aβ42 / Aβ40 ratio decreases, compared to results obtained from a control group, then the candidate substance, device, and / or composition may be selected for further investigation (e.g., as a potential therapeutic agent / device / composition for treating AD or inhibiting Aβ accumulation). Compared with results obtained from the control group, if the use of candidate substances, devices and / or compositions results in a reduction in amyloid deposition, neurofibrillary tangles, synaptic abnormalities (atrophy), neuronal cell death, and / or inflammatory response, then the candidate substances, devices and / or compositions may be selected for further investigation (e.g., as potential therapeutic agents / devices / compositions for treating AD, inhibiting Aβ deposition, inhibiting neurofibrillary tangles, inhibiting brain injury (e.g., neurodegeneration), or inflammatory responses). Learning function, memory function, cognitive function, synaptic function (e.g., synaptic transmission, synaptic plasticity, synaptic protein formation and / or function, and / or synaptic morphology), sensory function (e.g., olfaction, hearing, sensation, taste, touch, etc.), motor function (e.g., local motor function and muscle function, etc.), and emotional function (e.g., depression level) can also be compared between treatment and control groups treated with the candidate substance, device, and / or composition, for example, by performing animal behavioral analysis. For example, if significant improvements in learning and memory impairment, synaptic function, sensory function, motor function, and / or emotional function are observed after treatment with the candidate substance, device, and / or composition compared to the control group, the candidate substance, device, and / or composition can be selected for further research (e.g., as a potential therapeutic agent / device / composition for treating learning and memory impairment). In some cases, screening methods may also be performed using non-human animal tissues and / or cells according to this application, such as neurons, brain regions, or other tissues containing / corresponding to AD lesions, or portions thereof (e.g., olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, central nervous system, peripheral nervous system, spinal cord, cerebellum, skin tissue, muscle tissue, and / or visceral organs). For example, tissues and / or cells may be cultured in vitro or ex vivo, and then, after an appropriate incubation period, candidate substances, devices, and / or compositions may be applied to the cultured tissues and / or cells (e.g., for hours, days, weeks, or months), and the treated brain tissue / cells may be examined using the methods described above. In some cases, such as in methods for screening biomarkers, samples (e.g., cells, tissues, or other samples containing DNA or RNA, proteins, and / or metabolites) from non-human animals, parts thereof, or their offspring derived from this application, can be collected before and after the appearance of neurological diseases or symptoms-related indicators (e.g., Aβ deposition, neurofibrillary tangles, morphological or functional abnormalities (atrophy) synapses, neuronal cell death, or impaired memory and learning function). A comprehensive analysis of gene transcripts (transcriptome), gene translation products (proteome), lipids (lipome), or metabolites (metabolome) from the samples can then be performed to identify substances that have changed before and after the appearance of the relevant indicators. In some embodiments, the samples may contain bodily fluids from the non-human animal, such as rat blood or plasma (e.g., Plasma (containing exosomes), serum, urine, sweat, tears, saliva, semen, and / or cerebrospinal fluid. Nucleic acid microarrays, such as DNA microarrays, can be used to analyze gene transcripts (e.g., transcriptome); gel electrophoresis (e.g., two-dimensional gel electrophoresis) or mass spectrometry (e.g., time-of-flight mass spectrometry, electron spray ionization mass spectrometry, capillary HPLC / MS, and LC / MS / MS) can be used to analyze gene translation products (e.g., proteome); and NMR, capillary electrophoresis, LC / MS, and LC / MS / MS can be used to analyze metabolites (metabolome). When the presence / abundance of a substance shows a significant difference before and after the appearance of relevant indications, that substance can be considered a biomarker for neurological diseases or conditions, and can then be used for early diagnosis (especially preclinical diagnosis of neurological diseases or conditions). The identified biomarkers can be further detected using specific reagents or detection methods. For example, when the biomarker is a protein or peptide, it can be detected using specific antibodies via immunoassay. When the biomarker is a nucleic acid molecule (e.g., a transcription product), it can be detected using specific probes via Northern blot analysis or using specific primers via RT-PCR. Amyloid plaques can be detected by immunostaining with anti-P-amyloid antibodies (e.g., Cell Signaling Technology, 2454) and / or anti-P-amyloid oligomer antibodies (OMAB) (e.g., Agrisera, AS10932). In some embodiments, according to this application, Tau hyperphosphorylation can be detected in the non-human animals, portions thereof, tissues, or cells of this application. For example, Tau hyperphosphorylation may include or be revealed by increased phosphorylation of Tau's Thr231 and / or Ser202 compared to the corresponding wild-type non-human animals, cells, or tissues. In some cases, conformationally altered Tau proteins, such as oligomers and / or aggregates, can be detected in the non-human animals or portions thereof of this application. Tau protein oligomers and / or aggregates can be detected by staining with anti-MC1 antibody. In some cases, Tau protein oligomers and / or aggregates may co-localize with tubulin and / or microtubules in the non-human animals, tissues, or cells of this application. In some embodiments, neuronal loss can be detected in the non-human animals or portions thereof according to this application. For example, such neuronal loss may include neuronal apoptosis and / or neuronal necrosis (e.g., programmed necrosis). In some embodiments, apoptosis is revealed by detecting increased levels of Bax, Bcl-2, Cl-caspase3, and / or Pro-caspase3 in non-human animals, parts, tissues, or cells of this application compared to corresponding wild-type animal, tissue, or cell cultures. In some embodiments, necrosis (e.g., programmed necrosis) is detected by detecting increased levels of RIPK1 and / or pMLKL in non-human animals, parts, tissues, or cells of this application compared to corresponding wild-type animal, tissue, or cell cultures. In non-human animals, parts thereof (e.g., tissues, organs, or other parts), tissues, cells, or cell cultures, co-localization of necrotic bodies and microglia can be detected, as revealed by the co-localization of RIPK1 expression and Iba1 expression. In some cases, co-localization of necrotic bodies, microglia, and Aβ plaques can be detected, for example, by detecting co-expression of RIPK1 and Iba1 near or at the location of Aβ plaques, for example, through the use of anti-Iba1 antibody, anti-RIPK1 antibody, and 1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyrene]benzene. (l-Fluoro-2,5-bis[(￡)-3-carboxy-4-hydroxystyryl]benzene, FSB) are three labels. In non-human animals, parts thereof (e.g., tissues, organs, or other parts), tissues, cells, or cell cultures, co-localization of necrotic bodies and microglia can be detected, for example, as revealed by the co-localization of RIPK3 expression and Iba1 expression. In some cases, co-localization of necrotic bodies, microglia, and Aβ plaques can be detected, for example, by co-expression of RIPK3 and Iba1 in the vicinity or location of Aβ plaques, for example, by using three markers: anti-Iba1 antibody, anti-RIPK3 antibody, and FSB (1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyrene]benzene). In some embodiments, neuronal cell loss can be detected in non-human animals, parts thereof (e.g., tissues, organs, or other parts), tissues, cells, or cell cultures of this application. For example, a reduction in the number of Neu-N positive neurons can be detected in said non-human animals, parts thereof, tissues, cells, or cell cultures. In some embodiments, according to this application, gliosis can be detected in the non-human animal, its parts, cells, tissues, or cell cultures. Gliosis may include microgliosis and / or astrocyte proliferation. In some cases, microgliosis and / or astrocyte proliferation may be associated with amyloid plaques. For example, astrocytes and microglia may aggregate around amyloid plaques, and the number of astrocytes and microglia may also be increased. In some embodiments, according to this application, synaptic degeneration can be detected in the non-human animal, its parts, cells, tissues, or cell cultures. For example, synaptic degeneration can be revealed by swelling and / or cavitation of the postsynaptic density and / or the state / expression of synaptic markers. Such swelling and / or cavitation of postsynaptic density and / or presynaptic density can be detected by anti-PSD95 staining. The state / expression of such synaptic markers can be detected by anti-synaptophysin staining. In some embodiments, changes in brain morphology and / or weight can be detected in the corresponding wild-type non-human animal or its parts compared to the wild-type non-human animal. For example, changes in brain morphology and / or weight may include reduced brain volume, the appearance of ventricular cavitation and / or ventricular enlargement and / or hippocampal damage. For example, according to this application, a reduction in brain size can be detected in the non-human animal or its parts. In some implementations, cognitive impairment can be detected in the nonhuman animals compared to corresponding wild-type nonhuman animals. For example, cognitive impairment can be detected by the open field test, the Morris maze test, and / or the T-maze working memory test. Cognitive functions may include, for example, learning functions, memory functions, cognitive functions, sensory functions, motor functions, and / or emotional functions. Impaired learning function can be detected in the open field test, Morris maze test, and / or T-maze working memory test. For example, impaired memory function can be detected in the open field test, Morris maze test, and / or T-maze working memory test. Impaired cognitive function can be detected in the open field test, Morris maze test, and / or T-maze working memory test. For example, impaired sensory function can be detected in the open field test, Morris maze test, and / or T-maze working memory test. Disease or ailment In this application, the neurological disease or condition may include cognitive impairment. For example, the neurological disease or condition in this application may include neurodegenerative diseases or conditions. For example, the neurological disease or condition in this application may include mild cognitive impairment (MCI) and / or Alzheimer's disease. In this application, the neurodegenerative disease may include acute neurodegenerative diseases and chronic neurodegenerative diseases. For example, the neurodegenerative disease may include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In this application, the cognitive impairment can include early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. For example, the cognitive impairment can include cognitive impairment caused by normal aging. For example, the manifestations of early cognitive impairment (MCI) may include: loss of short-term memory, difficulty expressing or understanding abstract things, mood swings or behavioral changes, difficulty learning new things and following complex instructions, impaired judgment, and / or need for assistance with basic self-care. For example, the manifestations of intermediate cognitive impairment may include: confusion between long-term memory and current memory, difficulty expressing oneself, changes in behavior or personality, or emotional instability and / or need for assistance with self-care. For example, the manifestations of late cognitive impairment may include: memory loss, decline in physical activity and mental state, inability to express or communicate effectively, inability to care for oneself, and / or disruption of the biological clock. Without being limited by any theory, the embodiments described below are merely for illustrating the operation of the apparatus, methods and systems of this application, and are not intended to limit the scope of the invention. Example Example 1: Construction of a DIR-KI mouse model Construction strategy: Since the first 20 amino acids of mouse DDIT4L are identical to those of DIR, CRISPR / Cas9 technology was used to insert the nucleic acid sequence encoding the remaining 64 amino acids of DIR directly into the nucleic acid sequence encoding the 20th amino acid (aspartic acid) in the mouse DDIT4L genome via homologous recombination (Figure 1), so that the mouse can express human DIR normally (SEQ ID NO:1). In brief: First, Cas9 mRNA and sgRNA for knock-in (SEQ ID NO:6) were obtained via in vitro transcription. Then, a donor homologous recombination vector was constructed, containing approximately 3 kb of a 5' homologous arm (SEQ ID NO:16), a nucleic acid sequence encoding the last 64 amino acids of human DIR (SEQ ID NO:18), and approximately 3 kb of a 3' homologous arm (SEQ ID NO:17). Next, the Cas9-encoding mRNA, sgRNA, and donor vector were microinjected into fertilized eggs of C57BL / 6J mice to obtain F0 generation mice. Finally, F0 generation mice identified as positive by PCR were mated with C57BL / 6J mice to obtain positive F1 generation mice. Mating F1 generation mice yielded F2 generation wild-type, heterozygous, and homozygous mice. The body weight of homozygous (HO)DIR-KI mice was not significantly different from that of wild-type (WT) mice, indicating that the mutant mice had normal growth and metabolism (Figure 6A). Furthermore, there was no difference in walking distance and speed between WT and homozygous (HO)DIR-KI mice in the open field test, indicating that the motor function of the mutant mice was not altered (Figure 6B). Example 2 Identification of DIR-KI Mice Subsequently, the gene knock-in mice described in Example 1 were verified to express human DIR normally through various methods such as genome identification, mRNA identification, immunohistochemical staining, and protein detection. Genomic identification: Tail tissues of DIR-KI mice from Example 1 were collected, and genomic DNA was extracted using the TIANamp Genomic DNA Kit (TIANGEN). Identification primers P1 (SEQ ID NO: 7) and P2 (SEQ ID NO: 8) were designed, and the genotypes of the mice were identified by PCR combined with gel electrophoresis. A 476 bp PCR product was obtained from wild-type (WT) mice, two PCR products (476 bp and 671 bp) were obtained from DIR heterozygous (HE) mice, and a 671 bp PCR product was obtained from DIR homozygous (HO) mice (Figure 2, A). mRNA identification: Brain tissue from DIR-KI mice in Example 1 was collected and dispersed. Trizol (Sigma) reagent and isopropanol were added to extract mRNA. The extracted mRNA was washed with 70% ethanol solution, dried, and then dissolved in ultrapure water. One microgram of mRNA was taken and... II. The 1st Strand cDNA Synthesis Kit (Yisheng Biotechnology) reverse transcribed mRNA into cDNA. Primers P3 (SEQ ID NO:9), P4 (SEQ ID NO:10), and P5 (SEQ ID NO:11) were designed, and the expression of DDIT4L and DIR was identified by PCR. P3 and P4 were used to identify DDIT4L, and it was found that both wild-type mice and DIR-KI mice could normally express DDIT4L mRNA. P3 and P5 were used to identify DIR, and only DIR-KI mice could express DIR mRNA (Figure 2, B). Protein detection: Brain tissue from DIR-KI mice and wild-type mice was lysed with lysis buffer (50 mM Tris, 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, pH 7.4), centrifuged, and the supernatant was mixed with an appropriate amount of 4X loading buffer and denatured at 100℃ for 10 minutes. Finally, an appropriate amount of sample was used for Western blotting. The results showed that DIR protein could be detected in the brain tissue of DIR-KI mice (Figure 2, C). Immunohistochemical staining: Adult DIR-KI mice were anesthetized and perfused with PBS, followed by Lana's fixative (45mM NaH2PO4·2H2O, 115mM Na2HPO4·12H2O, 4% PFA, 14% saturated picric acid). Brain tissue was then removed and sectioned into approximately 50 μm thick sections using a Leica cryostat. Appropriate sections were affixed to gelatin-coated slides, blocked with donkey serum, and labeled with DIR antibody (Gier Biochemical). The DIR antibody was then further labeled with fluorescent secondary antibody. Finally, the labeled tissue sections were imaged using a Leica SP8 two-photon confocal microscope, revealing a high enrichment of DIR in neurons. Immunostaining of brain slices from homozygous (HO) DIR-KI mice showed that DIR was expressed in many neurons of the dentate gyrus (DG) of the hippocampus, some neurons in the CA1 and CA3 regions, and a few cortical and thalamic neurons (Fig. 2D, scale bar = 100 μm). Example 3: Physiological characteristics of DIR-KI mice The activity of neurons in DIR-KI mice was detected by electrophysiological recording, and the presence of p-Tau elevation and Aβ accumulation was determined by immunohistochemical staining. Immunohistochemical staining: Adult DIR-KI mice were anesthetized, perfused with PBS, and fixed with 4% paraformaldehyde solution. Brain tissue was then removed and sectioned into approximately 50 μm thick sections using a Leica cryostat. Appropriate sections were affixed to gelatin-coated slides, blocked with donkey serum, and labeled with p-Tau (Abcam, catalog number ab32057) and Aβ (Agrisera, catalog number AS0932) antibodies. Fluorescent secondary antibodies were then added to label the p-Tau and Aβ antibodies. Finally, the labeled tissue sections were imaged using a Leica SP8 two-photon confocal microscope. The results showed a significant increase in p-Tau and Aβ levels in the brain tissue of DIR-KI mice (Figure 3), and increased expression levels of Aβ and p-Tau in the dentate gyrus of the hippocampus of DIR-KI mice (Figure 3A, scale bar = 100 μm; Figure 3B, **, p < 0.01). Example 4: Behavioral characteristics of DIR-KI mice Various behavioral tests were used to verify whether DIR-KI mice exhibited memory impairment. Y-maze experiment: Mice were acclimatized to their environment for one week before the behavioral experiment. On the day of the experiment, mice were allowed to acclimatize to the experimental room 30 minutes beforehand. At the start of the experiment, mice were placed facing the wall on the starting arm A of the Y-shaped maze and allowed to freely explore the maze for 10 minutes. When in the center of the maze, mice could choose to enter in any direction. Cognitively normal mice tended to enter arms that had not been explored before. The entire process was recorded by video camera. After the experiment, the mice were returned to their cages. The experimental apparatus was cleaned with 75% alcohol during the experimental intervals. After the experiment, the order in which the mice explored the maze arms was manually recorded to calculate the total number of arm entries and the alternation ratio (alternation ratio = actual number of arm entries / (total number of arm entries - 2)). The experiment was double-blind for both the operator and the data analyst. The results showed that the DIR-KI mice exhibited weaker behavioral performance than wild-type mice, indicating a significant decline in working memory in DIR-KI mice (Figure 4, A). New Object Recognition Experiment: Mice were allowed to acclimatize to the experimental room 30 minutes before the experiment. The experiment consisted of an acclimatization period, a training period, and an experimental period. Acclimatization Period: Mice were removed from their cages and placed in the center of a plastic box, where they were allowed to freely explore the experimental area for 10 minutes. The training period followed 12-24 hours after the acclimatization period. Training Period: Two identical batteries were placed 5 cm from the wall. The mice were placed in the center of the area and allowed to freely explore for 10 minutes. The experimental period followed 3-4 hours after the training period. Experimental Period: A toy was randomly substituted for one battery, placed in the same position as the original object. The mice were placed in the center of the area and allowed to freely explore for 10 minutes. After the experiment, the mice were returned to their cages. The entire process was recorded using a camera. The experimental apparatus was cleaned with 75% alcohol during the experimental intervals. After the experiment, the time spent by the mice exploring both the old and new objects in the video recordings was manually counted, and the time recognition index for the new object was calculated. When the mouse's nose was within 2 cm of an object, and the mouse smelled or touched the object, it was considered an exploration behavior; biting or climbing on the object was not considered an exploration behavior. The recognition index of a mouse for a new object is calculated as follows: (Time spent exploring the new object - Time spent exploring the old object) / (Time spent exploring the new object + Time spent exploring the old object). Mice whose total exploration time is less than 15 seconds... Data will be excluded. The experiment was double-blind for both operators and data analysts. Results showed that DIR-KI mice had a weaker ability to recognize new objects than wild-type mice (Figure 4, B). Water Maze Experiment: Mice were acclimatized to the experimental room 30 minutes before the experiment. The experiment consisted of training and experimental days. Training days lasted 5-6 days, and the experimental day lasted 1 day. Before the experiment, the water tank was filled to a depth of 30 cm, and the water temperature was maintained at 19-22℃. Talcum powder was added to the water to make it cloudy. The water tank was divided into four directions: N, S, E, and W. The platform was placed in the NE quadrant. The mice were selected from a unique combination of S, W, NW, and SE for each day's water entry point. The room setup remained unchanged during the experiment. Specific patterns were affixed around the water maze as distal cues. The room lighting was indirect. The entire experiment was recorded by a camera, and the video recordings from the experimental day were analyzed using Etho Vision XT 14 software. Training Day: The platform was placed 0.5 cm underwater. The mice were entered into the water from the designated entry point, facing the tank wall, and a 1-minute timer was started. The timer stopped when the mouse reached the platform. If the mouse did not reach the platform within 1 minute, it was placed on the platform or guided onto the platform. After the mice remained on the platform for 30 seconds, they were removed, dried, and returned to their cages. A 30-minute interval was required before the next entry into the water. The mice were placed at a new entry point, and the experiment was repeated three times. The time taken for the mice to reach the platform was recorded each time. The experiment was repeated the following day. Training was conducted four times a day for a total of 5-6 days. Experimental Day: The experiment was conducted 24 hours after the end of the training day. The platform was removed. The mice entered the water from the SW quadrant, facing the tank wall. After 1 minute, the mice were removed, dried, and returned to their cages. After the experiment, Etho Vision XT 14 software was used to analyze the mouse behavior video recordings. Data collected included: escape latency to the target quadrant, number of times the mice crossed the platform location, and time spent in both the target and non-target quadrants. The experiment was double-blind for both the operator and the data analyst. The results showed that the number of times DIR-KI mice crossed the platform quadrant was significantly reduced, while the time spent entering the platform quadrant was significantly increased, indicating a weakened spatial memory ability in DIR-KI mice (Figure 4, C). Example 5: Disease model containing DIR functionally active fragments Electrophysiological recording of brain slices: Mouse brain tissue was placed in pre-cooled artificial cerebrospinal fluid (ACSF) and continuously filled with 95% O2 and 5% CO2. The tissue was then sliced ​​into approximately 350 μm thick sections using a Leica vibratory microtome. Suitable brain slices were selected and placed in observation chambers filled with ACSF. The observation chambers were fixed under a microscope and continuously perfused with fresh ACSF to maintain the viability of the brain tissue. Finally, postsynaptic currents emitted in the hippocampus were recorded using electrodes. Results showed that administration of the DIR-IR (SEQ ID NO:2) fragment of the hippocampal brain slice significantly reduced the amplitude of the postsynaptic current and also tended to decrease the frequency (Figure 5, A). The DIR-IR fragment was further divided into DIR-I (SEQ ID NO:4) and DIR-II (SEQ ID NO:5) parts, and their effects on postsynaptic currents were compared. After administration of the DIR-I fragment of the hippocampal brain slice, the amplitude of the postsynaptic current did not change significantly, but the frequency of the current decreased significantly (Figure 5, B). After administration of the DIR-II fragment to the hippocampus, the amplitude of the postsynaptic current tended to decrease, but the frequency of the current did not change significantly (Figure 5, C). Based on this, it can be inferred that the DIR fragment can at least partially or completely realize the function of the DIR. Example 6: The growth, metabolism, and motor function of the disease model remained unchanged. Weighing the mice revealed no significant difference between wild-type (WT) and homozygous (HO) mice, indicating that DIR knock-in does not affect the growth and metabolism of the mice (Figure 6, A). Open field experiment: Mice were allowed to acclimatize to the experimental room 30 minutes before the experiment. During the experiment, mice were removed from their cages and placed in the center of a plastic box, where they were allowed to freely explore the experimental area for 10 minutes. After the experiment, the mice were returned to their cages. The entire process was recorded using a camera. The experimental apparatus was cleaned with 75% alcohol during the experimental intervals. After the experiment, the video recordings were analyzed using Etho Vision XT 14 software to determine the time mice spent in the central and peripheral areas. The results showed no significant difference between wild-type (WT) and homozygous (HO) mice, indicating that the motor ability of the DIR knock-in mice was not altered. Example 7: DIR expression in homozygous (HO) DIR-KI mice under hypoxic conditions Hypoxia treatment: Mice were placed in laboratory mouse cages and kept under hypoxic conditions (8% oxygen) for 8 hours through the air inlet. An oxygen analyzer (Shanghai Precision Instruments Co., Ltd.) was used to detect the oxygen conditions in the cages through the air outlet to ensure the hypoxic conditions. Figure 7 shows the expression of DIR in homozygous (HO)DIR-KI mice under hypoxic conditions. DIR expression was significantly enhanced in the hippocampus of homozygous (HO)DIR-KI mice exposed to hypoxia (8% O2, 8 hours, n=5) for 8 hours (Figure 7A). For an ischemic model based on middle cerebral artery occlusion (MCAO) surgery, see Chiang, T., Messing, RO & Chou, WHMouse model of middle cerebral artery occlusion. J Vis Exp 48, 2761 (2011). Using unilateral middle cerebral artery occlusion (MCAO) in mice to simulate hypoxic-ischemic brain injury (n=4), DIR expression was significantly increased in the ipsilateral hippocampus of homozygous (HO) DIR-KI mice subjected to MACO, but not in the hippocampus of WT mice subjected to MACO (Figs. 7B-7C). Therefore, hypoxia can significantly enhance DIR expression in vivo. Example 8: Reversing AD-like pathological features with DIR antibody Using a DIR mAb (Gil Biochemical) that recognizes the last 27 AAs (PPLPLCRRCHKIHLRRLLSKFSNIFSP) of DIR, such as the A2D10 antibody, which has the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:19, the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:20, the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:21, the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:22; the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:24, the light chain variable region of the amino acid sequence shown in SEQ ID NO:25, the light chain variable region of the amino acid sequence shown in SEQ ID NO:27; the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:26; the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:27; the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:24; the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:25 ... heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of the heavy chain variable region of Homozygous (HO) DIR-KI mice were intraperitoneally injected with DIR mAb (0.5 mg / day) or IgG for 5 days. During the training phase of the Morris water maze test, mAb treatment reduced escape latency and improved working memory and novel object recognition (Fig. 8A, 8B). In probe tests used to assess spatial memory, mAb-treated mice had shorter entry latency and spent more time in the target quadrant (Fig. 8C). Furthermore, mAb treatment reduced the expression of Aβ and p-Tau (Fig. 8D, 8E), but did not significantly alter the expression of GFAP and IBA1 in the hippocampus of homologous DIR-KI mice. Homozygous (HO) The decrease in hippocampal LTP in DIR-KI mice could be rescued by intraperitoneal injection of mAb (0.5 mg / day, 5 days) (Figure 8F). In summary, these results indicate that inhibiting DIR activity with DIR mAb not only reduces Aβ and p-Tau levels but also reverses cognitive and memory impairments in homologous DIR-KI mice, demonstrating the important role of DIR in the pathogenesis of AD. The foregoing detailed description is provided by way of explanation and example and is not intended to limit the scope of the appended claims. Various variations of the embodiments described herein will be apparent to those skilled in the art and are reserved within the scope of the appended claims and their equivalents.

Claims

1. A non-human animal or a part thereof, comprising and / or expressing the intron-retained cleavage product DIR and / or a functionally active fragment thereof of DNA damage-inducible transcript 4-like transcript (DDIT4L).

2. The non-human animal or part thereof according to claim 1, wherein the DIR is derived from a human.

3. The non-human animal or part thereof according to any one of claims 1-2, wherein the DIR and / or its functionally active fragment comprises the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5.

4. The non-human animal or part thereof according to any one of claims 1-3, wherein the gene encoding the DIR and / or its functionally active fragment is homozygous or heterozygous.

5. The non-human animal or part thereof according to any one of claims 1-4, wherein the gene encoding the DIR and / or its functionally active fragment comprises the nucleic acid sequence shown in any one of SEQ ID NO:12-15.

6. The non-human animal or a portion thereof according to any one of claims 1-5, wherein the non-human animal is a gene-edited non-human animal or is derived from a gene-edited non-human animal.

7. The non-human animal or a portion thereof according to any one of claims 1-6, wherein the non-human animal is a gene-knock-in non-human animal or a non-human animal derived from a gene-knock-in non-human animal.

8. The non-human animal or a portion thereof according to any one of claims 1-7, wherein the expression of the DIR and / or its functionally active fragments is regulated by corresponding endogenous regulatory elements in the genome of the non-human animal.

9. The non-human animal or part thereof according to any one of claims 1-8, wherein the non-human animal is a non-human mammal.

10. The non-human animal or part thereof according to any one of claims 1-9, wherein the non-human animal is selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats.

11. The non-human animal or part thereof according to any one of claims 1-10, wherein the non-human animal is a rodent or a primate.

12. The non-human animal or a portion thereof according to any one of claims 1-11, wherein the portion comprises the organs, tissues and / or cells of the non-human animal.

13. The non-human animal or a part thereof according to any one of claims 1-12, wherein said part includes bodily fluids.

14. The non-human animal or part thereof according to claim 13, wherein the bodily fluid is selected from the group consisting of blood, plasma, serum, urine, sweat, tears, saliva, semen, and cerebrospinal fluid.

15. The non-human animal or part thereof according to claim 14, wherein the plasma comprises exosomes.

16. The non-human animal or a part thereof as claimed in any one of claims 1-15, wherein said part includes the brain or a portion thereof.

17. The non-human animal or a portion thereof according to claim 16, wherein the brain portion comprises brain regions selected from the group consisting of: olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, and cerebellum.

18. The non-human animal or a portion thereof according to any one of claims 1-17, wherein said portion comprises olfactory mucosa.

19. A non-human animal or a part thereof according to any one of claims 1-18, wherein said part comprises a part of the central nervous system, a part of the peripheral nervous system, skin tissue, muscle tissue and / or internal organs.

20. The non-human animal or part thereof according to claim 19, wherein the central nervous system includes the spinal cord.

21. The non-human animal or a portion thereof according to any one of claims 1-20, wherein the portion comprises cells, and the cells comprise cells selected from the group consisting of: primary neurons, microglia, astrocytes, oligodendrocytes, macrophages, perivascular epithelial-like cells, B cells, T cells, adult stem cells, NK cells, pluripotent stem cells, unipotent stem cells, embryonic stem cells, induced pluripotent stem cells, and gametes.

22. The non-human animal or part thereof according to claim 21, wherein the gametes comprise sperm and / or oocytes.

23. The non-human animal or a part thereof according to any one of claims 1-22, wherein the part cannot develop into a complete non-human animal.

24. The offspring or a portion thereof of the non-human animal according to any one of claims 1-23, wherein the offspring is obtained by hybridizing the non-human animal according to any one of claims 1-23 with another non-human animal, wherein the other non-human animal may or may not express the DIR and / or its functionally active fragments.

25. The offspring or a portion thereof according to claim 24, comprising and / or expressing the DIR and / or its functionally active fragments.

26. A descendant or a portion thereof according to any one of claims 24-25, wherein the portion is as described in any one of claims 12-23.

27. An isolated cell containing and / or expressing the intron-retained cleavage product DIR of DNA damage-inducing transcript 4-like transcript (DDIT4L) and / or its functionally active fragments.

28. The cell of claim 27, wherein the DIR is derived from human.

29. The cell according to any one of claims 27-28, wherein the DIR and / or its functionally active fragment comprises the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5.

30. The cell according to any one of claims 27-29, wherein the gene encoding the DIR and / or a functionally active fragment thereof is homozygous or heterozygous.

31. The cell according to any one of claims 27-30, wherein the gene encoding the DIR and / or a functionally active fragment thereof comprises the nucleic acid sequence shown in any one of SEQ ID NO:12-15.

32. The cell according to any one of claims 27-31, wherein it is a gene-edited cell or is derived from a gene-edited cell.

33. The cell according to any one of claims 27-32, wherein it is a gene knock-in cell or a cell derived from a gene knock-in cell.

34. The cell according to any one of claims 27-33, wherein the expression of said DIR and / or its functionally active fragments is regulated by corresponding endogenous regulatory elements in the cell genome.

35. The cell according to any one of claims 27-34, wherein it is a non-human animal cell.

36. The cell of claim 35, wherein the non-human animal is a non-human mammal.

37. The cell according to any one of claims 35-36, wherein the non-human animal is selected from: mouse, rat, rabbit, ape, monkey, pig, cow, sheep, horse, chicken, dog, alpaca and cat.

38. The cell according to any one of claims 35-37, wherein the non-human animal is a rodent or a primate.

39. The cell according to any one of claims 27-38, comprising cells selected from the group consisting of neuroblastoma cells, glioma cells, primary neurons, microglia, astrocytes, oligodendrocytes, macrophages, perivascular epithelioid cells, B cells, T cells, adult stem cells, NK cells, pluripotent stem cells, unipotent stem cells, embryonic stem cells, induced pluripotent stem cells, and gametes.

40. The cell of claim 39, wherein the gametes comprise sperm and / or oocytes.

41. The cell according to any one of claims 27-40, which cannot develop into a complete non-human animal.

42. An organization comprising and / or expressing the intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or its functionally active fragments.

43. The organization of claim 42, wherein the DIR is derived from a human.

44. The tissue according to any one of claims 42-43, wherein the DIR and / or its functionally active fragment comprises the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5.

45. The tissue according to any one of claims 42-44, wherein the gene encoding the DIR and / or a functionally active fragment thereof is homozygous or heterozygous.

46. ​​The tissue according to any one of claims 42-45, wherein the gene encoding the DIR and / or a functionally active fragment thereof comprises the nucleic acid sequence shown in any one of SEQ ID NO:12-15.

47. The tissue according to any one of claims 42-46, wherein it is a gene-edited tissue or is derived from a gene-edited tissue.

48. The tissue according to any one of claims 42-47, wherein it is a gene knock-in tissue or is derived from a gene knock-in tissue.

49. The tissue according to any one of claims 42-48, wherein the expression of said DIR and / or its functionally active fragments is regulated by corresponding endogenous regulatory elements in the genome of said tissue.

50. The tissue according to any one of claims 42-49, wherein it is a non-human animal tissue.

51. The organization of claim 50, wherein the non-human animal is a non-human mammal.

52. The tissue according to any one of claims 50-51, wherein the non-human animal is selected from: mice, rats, rabbits, apes, monkeys, pigs, cattle, sheep, horses, chickens, dogs, alpacas, and cats.

53. The organization according to any one of claims 50-52, wherein the non-human animal is a rodent or a primate.

54. The tissue according to any one of claims 50-53, comprising body fluids.

55. The tissue according to claim 54, wherein the body fluid is selected from the group consisting of blood, plasma, serum, urine, sweat, tears, saliva, semen, and cerebrospinal fluid.

56. The tissue of claim 55, wherein the plasma comprises exosomes.

57. The tissue according to any one of claims 42-56, comprising the brain or a portion thereof.

58. The tissue of claim 57, wherein the brain portion comprises brain regions selected from the group consisting of: the olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, cerebral cortex, medulla oblongata, and cerebellum.

59. The tissue according to any one of claims 42-58, comprising the olfactory mucosa.

60. The tissue according to any one of claims 42-59, comprising a portion of the central nervous system, a portion of the peripheral nervous system, skin tissue, muscle tissue, and / or visceral organs.

61. The tissue of claim 60, wherein the central nervous system comprises the spinal cord.

62. The tissue according to any one of claims 42-61, which cannot develop into a complete non-human animal.

63. A cell line or cell culture derived from a non-human animal or part thereof as claimed in any one of claims 1-23, a descendant as claimed in any one of claims 24-26, a cell as claimed in any one of claims 27-41, and / or a tissue as claimed in any one of claims 42-62.

64. The cell line or cell culture according to claim 63, wherein the cell culture is a primary cell culture.

65. The cell line or cell culture according to any one of claims 63-64, wherein the cell culture comprises organoids.

66. A composition comprising a non-human animal or a portion thereof as claimed in any one of claims 1-23, a progeny as claimed in any one of claims 24-26, a cell as claimed in any one of claims 27-41, a tissue as claimed in any one of claims 42-62, and / or a cell line or primary cell culture as claimed in any one of claims 63-65.

67. A kit comprising a non-human animal or part thereof as claimed in any one of claims 1-23, a progeny as claimed in any one of claims 24-26, a cell as claimed in any one of claims 27-41, a tissue as claimed in any one of claims 42-62, and / or a cell line or primary cell culture as claimed in any one of claims 63-65; and one or more additional components selected from the group consisting of: analytical buffers, controls, substrates, standards, assay materials, laboratory supplies, equipment, instruments, cells, organs, tissues, and user manuals or instructions.

68. A method for screening and / or identifying substances, devices, and / or compositions for the treatment, prevention, and / or prognosis of neurological diseases or conditions, the method comprising applying candidate substances, devices, and / or compositions to a nonhuman animal or part thereof as claimed in any one of claims 1-23, a progeny as claimed in any one of claims 24-26, a cell as claimed in any one of claims 27-41, a tissue as claimed in any one of claims 42-62, and / or a cell line or primary cell culture as claimed in any one of claims 63-65, and determining the effect of the candidate substances, devices, and / or compositions on one or more indicators of the neurological disease or condition.

69. A method of designing a substance, device, and / or composition for treating, preventing, and / or prognosing a neurological disease or condition, said method comprising: (i) applying the candidate substance, device, and / or composition to a non-human animal or part thereof as claimed in any one of claims 1-23, a progeny as claimed in any one of claims 24-26, a cell as claimed in any one of claims 27-41, a tissue as claimed in any one of claims 42-62, and / or a cell line or primary cell culture as claimed in any one of claims 63-65; (ii) determining the effect of the candidate substance, device, and / or composition on one or more indications of the neurological disease or condition; (iii) selecting candidate substances, devices, and / or compositions capable of preventing, inhibiting, and / or alleviating one or more of the indications of the neurological disease or condition; (iv) modifying the structure and / or composition of the candidate substance, device, and / or composition of step (iii) to obtain a modified substance, device, and / or composition having improved activity in treating, preventing, and / or prognosticating the neurological disease or condition.

70. The method according to any one of claims 68-69, wherein the neurological disease or condition includes cognitive impairment.

71. The method according to any one of claims 68-70, wherein the nervous system disease or condition includes neurodegenerative diseases or conditions.

72. The method according to any one of claims 68-71, wherein the neurological disease or condition includes mild cognitive impairment (MCI) and / or Alzheimer's disease.

73. The method according to any one of claims 68-72, wherein one or more indications of the neurological disease or condition include: Expression and / or accumulation of Aβ; expression and / or accumulation of APP fragments; Phosphorylation of Tau protein; Oligomerization and / or aggregation of Tau protein; changes in brain morphology and / or brain weight; The formation of neurofibrillary tangles in the brain; Changes in learning, memory, cognitive, sensory, motor, emotional, and / or synaptic functions; brain injury; neuronal loss, necrosome formation, neuronal death, changes in neuronal activity, neuronal apoptosis, neuronal necrosis, programmed neuronal cell death, decrease in the number of Neu-N positive neurons, and / or neurodegeneration; glial proliferation, microglia activation, astrocyte activation, and / or inflammatory responses; oxidative stress and / or mitochondrial dysfunction; vascular dysfunction; misfolded protein degradation and / or autophagy failure; and / or changes in brain glucose and / or lipid metabolism.

74. The method of claim 73, wherein the accumulation of Aβ comprises Aβ oligomerization and / or amyloid plaque formation.

75. The method of claim 73, wherein the APP segment comprises: sAPP, CTF-β, CTF-a and / or AICD.

76. The method of claim 73, wherein the synaptic function includes synaptic transmission, synaptic plasticity, formation and / or function of synaptic proteins, and / or synaptic morphology.

77. The method of claim 73, wherein the inflammatory response comprises a response by innate immune cells.

78. The method of claim 77, wherein the innate immune cells include T cells, B cells, NK cells, macrophages and / or dendritic cells.

79. The method of claim 73, wherein the vascular dysfunction includes amyloid angiopathy and / or blood-brain barrier (BBB) ​​damage.

80. The method according to any one of claims 68-79, wherein the apparatus comprises a medical device.

81. The method according to any one of claims 68-80, wherein the composition comprises a mixture derived from one or more organisms.

82. The method of claim 81, wherein the organism comprises plants, animals and / or microorganisms.

83. The method according to any one of claims 68-82, wherein the composition comprises tissue homogenate and / or blood sample.

84. A method for identifying potential biological targets and / or biomarkers that can be used to treat, prevent, and / or prognose neurological diseases or conditions, the method comprising: (i) Perform quantitative or qualitative proteomics, lipidomics and / or genomic comparative analysis on the non-human animal or part thereof as described in any one of claims 1-23, the offspring as described in any one of claims 24-26, the cell as described in any one of claims 27-41, the tissue as described in any one of claims 42-62, and / or the cell line or primary cell culture as described in any one of claims 63-65 with the corresponding control; (ii) identify genes, proteins and / or lipids with altered sequences, contents, expression levels, modifications and / or activities; (iii) wherein the genes, proteins and / or lipids identified in step (ii) are potential biological targets and / or biomarkers that can be used to treat, prevent and / or prognose the neurological diseases or conditions.

85. A method for screening biological targets and / or biomarkers for diagnosing and / or monitoring neurological diseases or conditions, the method comprising: Before and after the appearance of one or more related indicators of the neurological disease or condition, the presence and / or levels of various substances in samples obtained from non-human animals or parts thereof as claimed in any one of claims 1-23, offspring as claimed in any one of claims 24-26, cells as claimed in any one of claims 27-41, tissues as claimed in any one of claims 42-62, and / or cell lines or primary cell cultures as claimed in any one of claims 63-65 are determined to identify substances whose presence and / or levels change before and after the appearance of the indicators, and to identify such substances as the biological targets and / or the biomarkers.

86. The method of claim 85, wherein one or more indications of the neurological disease or condition include: Expression and / or accumulation of Aβ; expression and / or accumulation of APP fragments; Phosphorylation of Tau protein; Oligomerization and / or aggregation of Tau protein; changes in brain morphology and / or brain weight; The formation of neurofibrillary tangles in the brain; Changes in learning, memory, cognitive, sensory, motor, emotional, and / or synaptic functions; brain injury; neuronal loss, necrosome formation, neuronal death, changes in neuronal activity, neuronal apoptosis, neuronal necrosis, programmed neuronal cell necrosis, decrease in the number of Neu-N positive neurons, and / or neurodegeneration; glial proliferation, microglia activation, astrocyte activation, and / or inflammatory responses; oxidative stress and / or mitochondrial dysfunction; vascular dysfunction; misfolded protein degradation and / or autophagy failure; and / or changes in brain glucose and / or lipid metabolism.

87. The method according to any one of claims 84-86, wherein the neurological disease or condition includes cognitive impairment.

88. The method according to any one of claims 84-87, wherein the nervous system disease or condition includes neurodegenerative diseases or conditions.

89. The method according to any one of claims 84-88, wherein the neurological disease or condition includes mild cognitive impairment (MCI) and / or Alzheimer's disease.

90. The use of any non-human animal or part thereof as claimed in any one of claims 1-23, the offspring as claimed in any one of claims 24-26, the cell as claimed in any one of claims 27-41, the tissue as claimed in any one of claims 42-62, and / or the cell line or primary cell culture as claimed in any one of claims 63-65 in the preparation of an identification and / or screening system for identifying and / or screening substances, devices, compositions, biological targets and / or biomarkers for the treatment, diagnosis, prevention, monitoring and / or prediction of neurological diseases or conditions.

91. The non-human animal or part thereof as claimed in any one of claims 1-23, the offspring as claimed in any one of claims 24-26, the cell as claimed in any one of claims 27-41, the tissue as claimed in any one of claims 42-62, and / or the cell line or primary cell culture as claimed in any one of claims 63-65, which may be used to screen for substances, devices, compositions, biological targets and / or biomarkers for the treatment, diagnosis, prevention, monitoring and / or prediction of neurological diseases or conditions.

92. A method for preparing a non-human animal or a portion thereof as claimed in any one of claims 1-23, a cell as claimed in any one of claims 27-41, or a tissue as claimed in any one of claims 42-62, said method comprising causing the non-human animal or a portion thereof, cell, or tissue to contain and / or express said DIR and / or its functionally active fragments.

93. A method for preparing a disease model, the method comprising causing a non-human animal or a portion thereof, cell or tissue thereof to contain and / or express a DIR and / or a functionally active fragment thereof.

94. The method of claim 93, wherein the disease is a neurological disease or condition.

95. The method of claim 94, wherein the neurological disease or condition includes cognitive impairment.

96. The method according to any one of claims 94-95, wherein the nervous system disease or condition includes neurodegenerative diseases or conditions.

97. The method according to any one of claims 94-96, wherein the neurological disease or condition includes mild cognitive impairment (MCI) and / or Alzheimer's disease.

98. The method according to any one of claims 92-97, wherein the DIR and / or its functionally active fragment comprises the amino acid sequence shown in any one of SEQ ID NO: 1-2 and 4-5.

99. The method according to any one of claims 92-98, comprising knocking in a nucleic acid sequence encoding the DIR and / or a functionally active fragment thereof.

100. The method of claim 99, wherein the nucleic acid sequence encoding the DIR and / or its functionally active fragment comprises the nucleic acid sequence shown in any one of SEQ ID NO: 12-15.

101. The method according to any one of claims 99-100, wherein the knock-in comprises: In the presence of a donor nucleic acid molecule containing the said nucleic acid sequence, the genome of the non-human animal, cell, or tissue is exposed to the following substances: CRISPR-associated (Cas) proteins; and One or more ribonucleic acid (RNA) sequences, said RNA comprising: i) a portion complementary to the target site and ii) a binding site for said Cas protein.

102. The method of claim 101, wherein the binding site of the Cas protein comprises a tracrRNA sequence.

103. The method according to any one of claims 101-102, wherein the RNA sequence comprises the nucleic acid sequence shown in SEQ ID NO:

6.

104. The method according to any one of claims 99-103, wherein the knock-in further comprises culturing the cells or tissues under conditions in which the one or more RNA sequences hybridize with the target sequence, and the Cas protein cleaving the target sequence after the hybridization with the RNA sequence.

105. The method according to any one of claims 101-104, wherein the Cas protein is Cas9.

106. The method according to any one of claims 101-105, wherein the Cas protein is provided in the form of a protein, a messenger RNA (mRNA) encoding the Cas protein, or DNA encoding the Cas protein.

107. The method according to any one of claims 101-106, wherein the one or more RNA sequences are provided in the form of one or more RNA molecules or one or more DNA molecules encoding the RNA sequence.

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