Use of proton pump regulator in preparation of reagent

Abstract

The present application relates to use of a proton pump regulator in the preparation of a reagent. The proton pump regulator can regulate ATP6V1B2 and / or a functional active fragment thereof. The reagent can be used for preventing and / or treating diseases, including sleep disorders.

Description

Use of proton pump regulators in preparing reagents Technical Field The present application relates to the field of biomedicine, and specifically to the use of proton pump regulation in the preparation of reagents for preventing and / or treating sleep disorders. Background Art The ATP6V1B2 protein, encoded by the ATP6V1B2 gene, is a key structural component of the proton pump driven by ATP hydrolysis. It is widely distributed throughout human tissues, but is more abundant in the brain, kidneys, and osteoclasts. It plays a crucial role in synaptic transmission and lysosomal acidification. Mutations in the gene can cause DOORS syndrome (predisposed autosomal dominant congenital deafness with nail dysplasia syndrome). Reduced ATP6V1B2 protein expression may be associated with the development of AD. Sleep is the most basic physiological need of human beings. Sleep is not only an important way to maintain normal growth and development of the body, but also plays a vital role in the stability and integration of memory. In recent years, with the development of the economy and society, people have been affected by multiple factors such as increased work and life pressure and changes in lifestyle, and the problem of sleep disorders has become increasingly prominent. Sleep disorders can affect physical, psychological, social and emotional functions, and are common in adults and children of all ages. Existing drugs are known to regulate sleep through various mechanisms. For example, barbiturates, benzodiazepines, non-benzodiazepines, sedative antidepressants and other hypnotic drugs, but all types of drugs have the risk of addiction and drug tolerance caused by excessive use, and even side effects that are detrimental to health. Therefore, finding drugs that have no side effects, no adverse reactions and have good improvement or treatment effects on sleep disorders is an urgent problem that needs to be solved. Summary of the Invention The present application provides a proton pump regulator that regulates ATP6V1B2 and / or its functionally active fragments, and its use in preparing an agent for preventing and / or treating a disease, wherein the disease includes sleep disorders. On the one hand, the present application provides a proton pump regulator capable of regulating ATP6V1B2 and / or its functionally active fragments, and its use in preparing an agent for preventing and / or treating a disease, wherein the disease includes sleep disorders. In certain embodiments, the sleep disorder comprises parasomnias. In certain embodiments, the sleep disorder comprises insomnia, narcolepsy, sleep apnea, lower limb ataxia, nocturnal myoclonus, recurrent hypersomnia, post-traumatic hypersomnia, delayed sleep phase syndrome, delayed sleep cycle syndrome, and non-24-hour sleep-wake cycle disorder. In certain embodiments, the sleep disorder comprises adaptive insomnia, poor sleep habits, psychophysiological insomnia, somatic sleep disorder, psychiatric sleep disorder, insufficient sleep syndrome, drug-related sleep disorder and / or circadian rhythm sleep disorder. In certain embodiments, the sleep disorder comprises a sleep disorder associated with cardiovascular disease and / or neurological disease. In certain embodiments, the sleep disorder comprises a sleep disorder associated with stroke, a sleep disorder associated with cognitive impairment, and / or a sleep disorder associated with a neurodegenerative disease. In certain embodiments, the proton pump modulator is capable of regulating circadian rhythm. In certain embodiments, the proton pump modulator is capable of regulating wakefulness. In certain embodiments, the proton pump modulator is capable of regulating sleep-related substances in the body. In certain embodiments, the sleep-related substances include hormones and / or neurotransmitters. In certain embodiments, the sleep-related substance comprises a monoamine neurotransmitter. In certain embodiments, the sleep-related substances include one or more selected from the group consisting of melatonin, serotonin, norepinephrine, epinephrine, dopamine, growth hormone, cortisol, thyroid hormone, gonadotropin, sex hormone, insulin, leptin and / or ghrelin. In certain embodiments, the proton pump modulator is capable of modulating sleep. In certain embodiments, the proton pump modulator is capable of modulating the sleep state of non-rapid eye movement sleep and / or rapid eye movement sleep. In certain embodiments, the proton pump modulator can increase the number, duration and / or frequency of spindle waves during sleep. In certain embodiments, the proton pump modulator can increase the number, duration and / or frequency of spindle waves in the first sleep period. In certain embodiments, the proton pump modulator increases the frequency of rapid eye movement (REM) sleep at the end of the sleep cycle. In certain embodiments, the proton pump modulator increases the frequency of rapid eye movement (REM) sleep at the end of the first sleep cycle. In certain embodiments, the ATP6V1B2 and / or its functionally active fragments are derived from mammals. In certain embodiments, the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse. In certain embodiments, the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16. In certain embodiments, the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:5. In certain embodiments, the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO: 1. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11. In certain embodiments, the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 9 or 17. In certain embodiments, the proton pump modulator is capable of modulating proton pump activity and / or function. In certain embodiments, the proton pump modulator is capable of increasing the expression level and / or activity of a proton pump-related protein in a subject. In certain embodiments, the proton pump modulator is capable of regulating the expression level and / or activity of ATP6V1B2. In certain embodiments, the proton pump modulator is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject, wherein the increase comprises increasing the expression level and / or activity of ATP6V1B2 by at least about 10% compared to the original expression level and / or activity of ATP6V1B2 in the subject. In certain embodiments, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. In certain embodiments, wherein the proton pump modulator is capable of increasing neuronal synaptic transmitter release, the increase comprises an increase of at least about 10% compared to the level of native neuronal synaptic transmitter release in the subject. In certain embodiments, wherein the proton pump modulator increases the firing frequency of the excitatory postsynaptic current, the increase comprises an increase of at least about 10% compared to the original level of firing frequency of the excitatory postsynaptic current in the subject. In certain embodiments, the proton pump modulator comprises a protein and / or a polypeptide. In certain embodiments, the proton pump modulator comprises the amino acid sequence shown in SEQ ID NO: 19 or 99 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the proton pump modulator comprises an amino acid sequence shown in any one of SEQ ID NOs: 20-30, 93-98 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the proton pump modulator comprises an amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 31-41, 86-92 and / or variants thereof. In certain embodiments, the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 19, 42-48 and / or variants thereof. In certain embodiments, the proton pump modulator comprises a fusion protein and / or a fusion polypeptide. In certain embodiments, the fusion protein and / or fusion polypeptide comprises a molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing a cell membrane. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing the cell membrane comprises a polypeptide. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing the cell membrane comprises a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79-84 and / or variants thereof. In certain embodiments, the proton pump modulator comprises an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the proton pump modulator comprises an amino acid sequence as shown in any one of SEQ ID NOs: 72-78, 100-104 and / or variants thereof. In certain embodiments, the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-3 and / or variants thereof. In certain embodiments, the proton pump modulator comprises a multimer. In certain embodiments, the multimer comprises a homodimer. In certain embodiments, the cysteine ​​in the amino acid sequence of the proton pump modulator does not have a sulfhydryl blocking modification. In certain embodiments, the serine in the amino acid sequence of the proton pump modulator does not have a phosphorylation modification. In certain embodiments, the subject comprises a mammal. In certain embodiments, the subject comprises a human. In certain embodiments, the agent is formulated for oral administration and / or injection. On the other hand, the present application provides a proton pump regulator, which regulates ATP6V1B2 and / or its functionally active fragments, and its use in preventing and / or treating sleep disorders. In another aspect, the present application provides a method for preventing and / or treating sleep disorders, comprising administering an effective amount of a proton pump regulator to a subject in need thereof. Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of this application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application relates. Accordingly, the descriptions in the drawings and specification of this application are merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The specific features of the inventions of this application are set forth in the appended claims. The features and advantages of the inventions of this application can be better understood by referring to the exemplary embodiments described in detail below and the accompanying drawings. A brief description of the drawings is as follows: FIG1A-FIG1B shows the results of co-immunoprecipitation of the ATP6V1B2 regulator (QD202) described in the present application with the ATP6V1B2 protein. FIG2 shows the results of co-immunoprecipitation of the ATP6V1B2 regulators (QD202(D15A), QD202(V16A) mutants) described in the present application with the ATP6V1B2 protein. FIG3A-FIG3B show the effects of the ATP6V1B2 modulator (QD202) described herein on spontaneous excitatory postsynaptic currents. FIG4A to FIG4F show the effects of the ATP6V1B2 modulators described herein (QD202 N′-1, QD202 C′-1, QD202 C′-2) on spontaneous excitatory postsynaptic currents. FIG5 shows the effect of the ATP6V1B2 modulator (QD202 mutant 1) described herein on spontaneous excitatory postsynaptic currents. 6A-6B show the effects of ATP6V1B2 modulators described herein using different delivery molecules on spontaneous excitatory postsynaptic currents. 7A-7D show the effects of the ATP6V1B2 modulators described herein on sleep-related substances. Figures 8A-8C show sleep monitoring results for mice, demonstrating that the ATP6V1B2 modulators described herein can improve sleep. Figure 8A is a typical example of EEG, EMG, and EEG power density for 10 seconds during NREM or REM sleep or wakefulness in mice, Figure 8B shows the sleep monitoring results for control mice, and Figure 8C shows the sleep monitoring results for 12 hours after administration of the ATP6V1B2 modulators described herein. DETAILED DESCRIPTION The following describes the implementation of the present invention through specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Definition of terms In this application, the term "ATP6V1B2" generally refers to the ATPase H+ transporting V1 subunit B2 protein (or ATPase H+ transporting V1 subunit B2) (or ATP6B2, DOOD, HO57, VATB, VPP3, Vma2 or ZLS2), and the gene encoding the protein. The ATP6V1B2 can be a multi-subunit enzyme that mediates acidification of organelles in eukaryotic cells. The ATP6V1B2 can be involved in processes such as protein sorting, zymogen activation, receptor-mediated endocytosis and synaptic vesicle proton gradient generation. The ATP6V1B2 protein can include a cytoplasmic V1 domain and a transmembrane V0 domain. The accession number of human ATP6V1B2 in GenBank is 526. The accession number of human ATP6V1B2 in UniProt can be P21281. In this application, the term "proton pump-associated protein" generally refers to proteins that encode and / or express proton pumps. The proton pumps can be proteins that actively transport hydrogen ions across a biological membrane against the electrochemical potential difference between hydrogen ions on either side of the membrane. These proton pumps can include Na-K pumps, Ca2+ pumps, H+-ATP pumps, and H+ pyrophosphate pumps. In this application, the term "modulator" generally refers to a compound that changes the expression and / or activity of a molecule. For example, a modulator can include a compound that increases or decreases the intensity and / or expression of a certain activity of a molecule compared to the intensity and / or expression of the activity in the absence of the modulator. For example, the modulator can include an agonist that increases the intensity and / or expression of one or more activities of a molecule. In this application, the term "binding agent" generally refers to a natural or non-natural molecule that specifically binds to a target or a portion of a target. Binding agents can include small molecule compounds, polymers, and / or biomacromolecules. Binding agents can include proteins, peptides, nucleic acids, sugars, lipids, and small molecule compounds. For example, a binding agent can include a polypeptide. For example, a binding agent can include a fusion polypeptide. In the present application, the term "expression level" generally refers to the protein, RNA or mRNA level of a specific related gene. Any method known in the art can be used to measure the expression level of a specific related gene (such as human ATP6V1B2 gene). In the present application, "expression" generally refers to the process in which the information encoded by a gene is converted into a structure present in a cell and operated in a cell. For example, reverse transcription and amplification analysis (such as PCR, connection RT-PCR or quantitative RT-PCR) can be included, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining or mass spectrometry can be included. Analysis can be performed directly on a biological sample or on the protein / nucleic acid separated from the sample. In this application, the term "activity" generally refers to any activity associated with a particular protein. In this application, the activity may include, for example, any activity associated with the ATP6V1B2 protein. The activity may include an enzymatic activity associated with a protease. In some cases, the activity may include a biological activity. In some cases, the activity may include binding of the protein to a receptor, for example, where the binding may produce a measurable downstream effect. In this application, the activity may include any activity that would be attributed to the protein by one skilled in the art. In this application, the term "variant" generally refers to a polypeptide comprising 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 higher (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, the comparison being performed by sequence alignment and determining 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., 215: 403-410).

[1990] ). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI). In the present application, the "variant" and / or "functional variant" can be, for example, a protein or polypeptide in which one or more amino acids are substituted, deleted or added in the amino acid sequence of the protein and / or the polypeptide (e.g., a binder that binds to ATP6V1B2 or a fragment thereof). For example, the variant may comprise a protein or polypeptide that has been subjected to amino acid changes by at least 1, for example, 1-30, 1-20 or 1-10, for example, 1, 2, 3, 4 or 5 amino acid substitutions, deletions and / or insertions. The functional variant may substantially retain the biological properties of the protein or polypeptide before the change (e.g., substitution, deletion or addition). For example, the functional variant may retain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (e.g., the ability to bind to ATP6V1B2) of the protein or polypeptide before the change. For example, the substitution may be a conservative substitution. For example, the variant may also be a polypeptide encompassing its functionally active fragments, and is not limited to polypeptides comprising the functionally active fragments of the protein produced after processing and / or modification in the cell. In the present application, the "variant" may be a homolog. The homolog may be a protein or polypeptide having at least about 85% (e.g., at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence of the protein and / or polypeptide (e.g., a binding agent that specifically binds to ATP6V1B2 or a fragment thereof). In the present application, described homology generally refers to the similarity, similarity or association between two or more sequences.Can calculate " sequence homology per-cent " in the following manner: two sequences to be compared are compared in comparison window, determine that there is identical nucleic acid base (for example, A, T, C, G, U) or identical amino acid residue (for example, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) number in the position to obtain the number of matching positions, with the number of matching positions divided by the total number of positions (that is, window size) in the comparison window, and result is multiplied by 100, to produce sequence homology per-cent.Comparison carried out in order to determine the sequence homology per-cent, can realize by several ways known in the art, for example, use publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length of the sequences being compared or within a region of interest. Homology can also be determined by the following methods: FASTA and BLAST. A description of the FASTA algorithm can be found in W. R. Earson and D. J. Lipman, "Improved tools for biological sequence comparison," Proc. Natl. Acad. Sci., 85: 2444-2448, 1988; and D. J. Lipman and W. R. Earson, "Rapid and sensitive protein similarity search," Science, 227: 1435-1441, 1989. A description of the BLAST algorithm can be found in S. Altschul, W. Gish, W. Miller, E. W. Myers, and D. Lipman, "A basic local alignment search tool," J. Mol. Biol., 215: 403-410, 1990. In this application, the term "amino acid" generally refers to naturally occurring, synthetic, or non-natural amino acids, as well as amino acid analogs and amino acid mimetics that function in a similar manner to naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; analogs, derivatives, and congeners thereof; amino acid analogs with variant side chains; and stereoisomers of any of the foregoing. The 20 commonly used amino acids and their abbreviations used in this application are conventionally used. See Immunology-A Synthesis (2nd edition, ES Golub and DR Gren, eds., Sinauer Associates, Sunderland, Mass. (1991)), the contents of which are incorporated herein by reference. This application uses commonly used amino acid single-letter abbreviations and three-letter abbreviations (Bruce Alberts et al., Molecular Biology of the Cell, Garland Publishing, Inc., New York (4th edition, 2002)). In this application, the term "conservative replacement" or "conservative substitution", also known as "conservative mutation", generally refers to the substitution of an amino acid with another amino acid having similar properties (such as charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation and rigidity, etc.) in a protein. Examples of amino acid groups having side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxy side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine and tryptophan; 5) basic side chains: lysine, arginine and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine ​​and methionine. Conservative amino acid substitution groups can be, for example, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. In this application, the term "non-conservative substitution" is also referred to as "radical replacement" or "radical substitution", which generally refers to the substitution of an amino acid with another amino acid having different properties in the protein (e.g., charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation and rigidity, etc.). For example, non-conservative substitution can also involve the use of unnatural amino acids. In the present application, the term "polar amino acid" can include polar uncharged amino acids, basic (positively charged) amino acids, acidic (negatively charged) amino acids. For example, polar amino acids can include threonine, serine, cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid. In the present application, the term "non-polar amino acids" may include phenylalanine, proline, valine, leucine, isoleucine, methionine, tryptophan, alanine, glycine. In the present application, the term "fusion polypeptide" generally refers to a polypeptide that comprises at least two discrete peptides or polypeptides (which do not exist together in this way in natural polypeptides, that is, these parts do not naturally exist in the same polypeptide or in the same order), or is composed of at least two discrete peptides or polypeptides (which do not exist together in this way in natural polypeptides, that is, these parts do not naturally exist in the same polypeptide or in the same order). The discrete peptides or polypeptides can be linked together directly or indirectly to form a fusion polypeptide. For example, the discrete peptides or polypeptides can be linked to form a fusion polypeptide by peptide bonds. For example, the discrete peptides or polypeptides can be linked to form a fusion polypeptide by a linker. For example, the fusion polypeptide described in the present application may include a fusion polypeptide formed by connecting a polypeptide capable of binding to ATP6V1B2 and a polypeptide having a specific function. In the present application, the term "fusion protein" generally refers to a protein composed of two or more polypeptides. In this application, term " blood-brain barrier (BBB) ​​" generally refers to the physiological barrier between peripheral circulation and brain and spinal cord, which is composed of the end feet of brain capillary endothelial cells, basement membrane and glial cells, forming a tight barrier that limits molecules, even very small molecules (such as urea (60 daltons)) are transported to the brain. The BBB in the brain, the blood-spinal cord barrier in the spinal cord and the blood-retinal barrier in the retina are continuous capillary barriers in the CNS, and are collectively referred to as blood-brain barrier or BBB in this article. BBB also encompasses blood-CSF barrier (choroid plexus), wherein the barrier is composed of ependymal cells rather than capillary endothelial cells. In this application, the term "penetrating peptide" generally refers to a class of short peptides that can cross cell membranes or tissue barriers. For example, penetrating peptides can carry biomacromolecules such as proteins, RNA, and DNA into cells through mechanisms such as endocytosis and direct penetration to exert their effector functions. In this application, the term "polymer" generally refers to a molecule having two or more polypeptide chains associated by covalent, non-covalent, or both covalent and non-covalent interactions. The polymer may include a dimer. In this application, the term "homodimer" generally refers to a molecule formed by two identical monomers. These two identical monomers can aggregate, complex or associate with each other through covalent and / or non-covalent interactions. In this application, the term "sulfhydryl blocking" generally refers to blocking free sulfhydryl groups to prevent the formation of intramolecular and / or intermolecular disulfide bonds. In this application, the sulfhydryl blocking can occur on cysteine ​​residues. The sulfhydryl blocking can prevent the formation of disulfide bonds between cysteine ​​residues of the protein, thereby preventing the protein from being cross-linked or modified. The sulfhydryl blocking can be achieved by using a blocking agent, which can be a reducing agent. The blocking agent can include dithiothreitol (DTT), β-mercaptoethanol (BME), and tris(2-carboxyethyl)phosphine hydrochloride (TCEP·HCl). In this application, the term "serine phosphorylation" generally refers to a phosphorylation modification that occurs on a serine residue. The serine phosphorylation can be a process in which a phosphate group from a donor (e.g., ATP or GTP) is transferred to a serine residue. The serine phosphorylation can be mediated by a protein kinase. The serine phosphorylation can result in changes in protein activity. In this application, the term "isolated" generally refers to a substance obtained artificially from its natural state. For example, a polynucleotide or polypeptide naturally present in a living animal, which has not been isolated, and a highly purified identical polynucleotide or polypeptide isolated from this natural state can be considered isolated. The term "isolated" does not exclude the presence of artificial or synthetic substances, nor does it exclude the presence of other impurities that do not affect the activity of the substance. In this application, the term "nucleic acid molecule" generally refers to isolated forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof, isolated from their natural environment or artificially synthesized. In this application, the term "vector" generally refers to a nucleic acid delivery vehicle into which a polynucleotide encoding a protein can be inserted and used to express the protein. A vector can transform, transduce, or transfect host cells, allowing the genetic material it carries to be expressed within the host cells. A single vector may contain multiple elements that control expression. Furthermore, a vector may contain an origin of replication. A vector may also include components that facilitate its entry into cells. In this application, the term "cell" generally refers to a single cell, cell line or cell culture that may be or has been a recipient of a subject's plasmid or vector, including a nucleic acid molecule as described herein or a vector as described herein. A cell may include the offspring of a single cell. Due to natural, accidental or intentional mutations, the offspring may not necessarily be identical to the original parent cell (in terms of the morphology of the total DNA complement or in the genome). A cell may include a cell transfected in vitro with a vector as described herein. In this application, the term "immunoconjugate" generally refers to a substance formed by linking a polypeptide with other active agents, which may be small molecule active agents, such as therapeutic agents, imaging probes, or spectroscopic probes. In this application, the term "pharmaceutical composition" generally refers to a composition used to prevent / treat a disease or condition. The pharmaceutical composition may include the isolated polypeptide described herein, the nucleic acid molecule described herein, the vector described herein, and / or the cell described herein, and optionally a pharmaceutically acceptable carrier. In addition, the pharmaceutical composition may also include one or more (pharmaceutically effective) carriers and other suitable formulations. The acceptable ingredients of the composition may be non-toxic to the recipient at the dosage and concentration used. The pharmaceutical composition of the present application includes, but is not limited to, liquid, frozen, and lyophilized compositions. In this application, the term "pharmaceutically acceptable carrier" generally refers to a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to cells or mammals exposed thereto at the doses and concentrations employed. Physiologically acceptable carriers may include suitable substances. Pharmaceutically acceptable carriers are generally not the same substance as vectors used to insert nucleic acids in genetic engineering. In this application, the term "specific binding" or "specific" generally refers to a measurable and reproducible interaction, such as binding between a target and an antibody, that can determine the presence of a target in the presence of a heterogeneous population of molecules (including biomolecules). For example, an antibody that specifically binds to a target (which may be an epitope) may be one that binds to that target with greater affinity, avidity, more readily, and / or for a greater duration than it binds to other targets. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among proteins of different species. In certain embodiments, specific binding may include, but does not require, exclusive binding. In this application, the term "neuron" generally refers to a nerve cell, which is the main functional unit of the nervous system. A neuron can be composed of a cell body and its protrusions, an axon, and one or more dendrites. Neurons can transmit information to other neurons or cells by releasing neurotransmitters at synapses. In this application, the term "transmitter release" generally refers to neurotransmitter release, that is, a neuron releases a neurotransmitter (Neurotransmitter) encapsulated in a vesicle into the synaptic cleft, which acts on another neuron to transmit information. In the transmitter release process, the basic structure of the neural circuit, the synapse (Synapse), may be involved. In some cases, the transmitter release can be referred to as synaptic transmission (Synaptic transmission). The method of transmitter release can include synchronous release (Synchronous release), asynchronous release (Asynchronous release) and spontaneous release (Spontaneous release). In this application, the term "excitatory postsynaptic current (EPSC)" generally refers to the ion flow that causes an excitatory postsynaptic potential (EPSP). The EPSP is a postsynaptic potential that makes it easier for the postsynaptic neuron to trigger an action potential. This temporary depolarization of the postsynaptic membrane potential caused by the influx of positively charged ions into the postsynaptic cell is the result of opening ligand-gated ion channels. The frequency and / or amplitude of the EPSC can be recorded using voltage clamping. In this application, the term "discharge frequency" generally refers to the discharge frequency of action potentials. Action potential can refer to the rapid and reversible reversal and recovery process of the potential on both sides of the membrane generated on the basis of the resting potential when an excitable cell is stimulated. The action potential can be composed of a peak potential and an afterpotential, corresponding to the depolarization (Depolarisation) and hyperpolarization (Hyperpolarization) processes respectively. The discharge of action potentials can have the characteristics of pulses. In some cases, the discharge frequency of pulses is the ratio of the number of pulse discharges to the time. For example, the discharge frequency can include the discharge frequency of synaptic vesicles releasing neurotransmitters. For example, the discharge frequency can include the discharge frequency of excitatory postsynaptic currents. In the present application, term " cognitive impairment " generally refers to be thought of or indeed involve the progressive loss (comprising neuronal death) of neuronal structure and / or function or the above-mentioned relevant disease and illness.For example, the feature of described cognitive impairment can comprise the damage of cognition (for example, memory, attention, perception and / or thinking).These obstacles can comprise pathogen-induced cognitive dysfunction, for example the cognitive dysfunction that HIV is relevant and the cognitive dysfunction that Lyme disease is relevant.The example of cognitive impairment can comprise Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), autism, early cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and / or memory impairment (AAMI) relevant to age. In this application, the term "neurodegenerative disease" generally refers to cognitive disorders such as dementia caused by the gradual loss of neuronal structure and function, including neuronal death and glial cell balance. In some cases, age (e.g., Alzheimer's disease (AD), Parkinson's disease (PD)) or genetic mutations that affect CNS cell function (e.g., Huntington's disease, early-onset AD or PD, amyotrophic lateral sclerosis (ALS)) can cause the neurodegenerative disease. The neurodegenerative disease may have changes and / or conditions selected from the following: protein misfolding and aggregation; neuroinflammation (e.g., CNS inflammation that occurs under toxic stimulation (e.g., protein aggregation), infection, traumatic injury, or autoimmunity); changes in cell signal transduction; acquired aging / cell death (e.g., interrupted apoptosis signal transduction, mitochondrial dysfunction, impaired autophagy, and necrotic bodies activated by stress / inflammation); motor cell damage and epigenetic changes. In this application, the term "stroke" or "stroke" generally refers to a condition caused by cell death due to blockage or bleeding of one or more blood vessels supplying blood to the brain, including stroke and damage caused by stroke. For example, stroke can be an acute cerebrovascular disease. In this application, "ischemic stroke" generally refers to a stroke caused by blockage of one or more blood vessels supplying blood to the brain. Ischemic stroke can be caused by thrombosis, embolism and / or hypotension. Thrombosis can be caused by atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm. Ischemic stroke includes cerebral infarction, which can include lacunar infarction, ischemic cerebral infarction and / or hemorrhagic infarction. The types of ischemic stroke can include, for example, embolic stroke, cardioembolic stroke, thrombotic stroke, large vessel stroke, lacunar infarction, artery-artery stroke and cryptic stroke. In this application, "hemorrhagic stroke" generally refers to a stroke caused by bleeding from one or more blood vessels supplying blood to the brain. Hemorrhagic stroke can include intraparenchymal hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage. Hemorrhagic stroke can include primary cerebral hemorrhage and / or secondary cerebral hemorrhage. Hemorrhagic stroke can include aneurysmal subarachnoid hemorrhage. Hemorrhagic stroke can be caused by vascular malformations, aneurysms, blood diseases, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy and / or aneurysmal stroke. In this application, the term "sleep disorder" is generally used to describe abnormal conditions that occur during a subject's sleep. Normal sleep consists of two states: non-rapid eye movement (NREM) and rapid eye movement (REM). One NREM and REM sleep cycle lasts approximately 90-120 minutes. A normal person goes through approximately 4-6 such sleep cycles per night, with NREM accounting for approximately 75%-80% of an adult's total sleep time. It can be divided into three stages: N1, N2, and N3, as sleep depth changes. Heart rate, body temperature, and muscle tension typically decrease as sleep deepens. Most people experience an alpha rhythm in their EEG when awake with their eyes closed. After entering stage N1, the EEG is replaced by low-voltage mixed-frequency waves. Stage N2 sleep EEG displays characteristic K complexes and / or sleep spindles. Stage N3 exhibits high-amplitude slow wave activity, also known as slow-wave sleep. This is deep sleep, so the awakening threshold is higher, and it is also commonly referred to as a high-quality sleep period. REM sleep occurs after each NREM sleep, usually accounting for 20%-25% of total sleep. It is characterized by rapid eye movements and the lowest muscle tone of the entire sleep period, but there are significant fluctuations in respiratory rate, depth, and heart rate. Most fantastic dreams occur during this period. The subject's sleep state can be monitored by methods known in the art, such as polysomnography (PSG). Polysomnography can include a comprehensive analysis of nighttime sleep conditions by synchronously monitoring parameters such as electroencephalogram (EEG), electrooculogram (EOG), electromyogram (EMG), respiratory airflow, chest and abdominal movements, snoring, electrocardiogram (ECG), blood oxygenation, body position, audio / video, etc. Sleep staging usually refers to analyzing the subject's EEG, electrooculogram, and muscle tone every 30 seconds according to the American Academy of Sleep Medicine's sleep staging rules after monitoring the sleep state, in order to evaluate the subject's sleep structure and quality. According to one classification scheme, such as the International Classification of Sleep Disorders (ICSD), third edition, ten major categories of sleep disorders have been identified: (1) insomnia, (2) sleep-related breathing disorders, (3) central hypersomnias, (4) sleep-wake circadian rhythm disorders, (5) parasomnias, (6) sleep-related movement disorders, and (7) other sleep disorders. Within each of these broad categories, multiple subcategories are identified. Each category and subcategory is defined as a "disorder." According to another classification scheme, six major categories of sleep disorders have been identified: (1) insomnia, (2) hypersomnia, (3) parasomnias, (4) circadian rhythm sleep-wake disorders, (5) sleep-related breathing disorders, and (6) sleep movement disorders. Within each of these major categories, multiple subcategories are identified. Each category and subcategory is defined as a "disorder." According to another classification scheme, ten major categories of sleep disorders have been identified: (1) insomnia disorder, (2) hypersomnia disorder, (3) narcolepsy, (4) breathing-related sleep disorders, (5) circadian rhythm sleep-wake disorders, (6) non-REM sleep arousal disorders, (7) nightmare disorders, (8) REM sleep behavior disorder, (9) restless legs syndrome, and (10) substance / medication-induced sleep disorders. Within each of these major categories, multiple subcategories are identified. Each category and subcategory is also defined as a "disorder." According to another classification scheme, four major categories of sleep disorders have been identified: (1) parasomnias, (2) parasomnias, (3) circadian rhythm sleep disorders involving sleep timing, and (4) sleep disorders caused by medical or psychological conditions. Within each of these major categories, multiple subcategories are identified. Each category and subcategory is also defined as a "disorder." Parasomnias generally involve difficulty falling asleep, maintaining sleep, or excessive sleepiness, and are primarily disorders of initiating or maintaining sleep or excessive sleepiness, characterized by disturbances in the amount, quality, or timing of sleep. Parasomnias can be further divided into: intrinsic parasomnias, extrinsic parasomnias, and circadian rhythm sleep disorders. Intrinsic sleep disorders can include idiopathic hypersomnia, narcolepsy, periodic limb movement disorder, restless legs syndrome (also known as lower limb hypoventilation), obstructive sleep apnea, central sleep apnea syndrome, sleep state misinterpretation, psychophysiological insomnia, recurrent hypersomnia, post-traumatic hypersomnia, and central alveolar hypoventilation syndrome. Exogenous sleep disorders can include alcohol dependence insomnia, food allergy insomnia, and inadequate sleep habits. Circadian rhythm sleep disorders can include advanced sleep phase syndrome, delayed sleep phase syndrome, jet lag, and shift work sleep disorder. The quality and quantity of sleep can be assessed through indicators such as bedtime, sleep latency (from bedtime to sleep onset), number and duration of awakenings, last awakening time and rise time in the morning, frequency and duration of naps, and sleep quality. Sleep status can be assessed using sleep scales such as the Sleep Dysfunction Rating Scale (SDRS) and the Pittsburgh Sleep Quality Index (PSQI). Polysomnography and actigraphy are also commonly used tests for diagnosing sleep disorders. In this application, "insomnia" or "insomnia disorder" are used interchangeably and generally refer to a symptom in which it is difficult to fall asleep naturally. It may be difficult to fall asleep (difficulty falling asleep) or difficult to maintain deep sleep for a long time (difficulty maintaining sleep). Insomnia disorders include "adult insomnia", that is, adults cannot fall asleep at the expected bedtime; "child insomnia", that is, children (i.e., people 12 years of age and younger) cannot fall asleep at the expected bedtime, for example because they refuse to go to bed or are unwilling to let their parents leave their bedside; and middle of the night insomnia (or "MOTN insomnia"), that is, waking in the middle of the night and having difficulty continuing to sleep, sometimes also called sleep maintenance insomnia, mid-term insomnia, middle of the night awakening (or "MOTN awakening") and / or night awakening. As used in this application, "adult insomnia" is sometimes also called sleep onset insomnia, insomnia disorder, "primary insomnia", or early insomnia, to distinguish it from the non-specific term insomnia. In some cases, adult insomnia is not caused by illness or substance use / abuse. Adult insomnia can be assessed by prolonged LPS. MOTN insomnia can be assessed by prolonged WASO and / or increased number of awakenings ("NAW"). The diagnostic criteria for insomnia can refer to the standards known in the art. For example, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) states that the diagnostic criteria for insomnia are as follows: The patient's complaint mentions dissatisfaction with the length and quality of sleep and is related to at least one of the following statements: difficulty falling asleep; difficulty maintaining sleep, often waking up suddenly in the middle of sleep or having difficulty falling asleep again once waking up; getting up too early and having difficulty falling asleep again. In the present application, sleep disorders may include insomnia, narcolepsy, sleep apnea, lower limb ataxia, nocturnal myoclonus, recurrent hypersomnia, post-traumatic hypersomnia, delayed sleep phase syndrome, sleep cycle syndrome and non-24-hour sleep-wake cycle disorder. For example, sleep disorders may include adaptive insomnia, poor sleeping habits, psychophysiological insomnia, somatic sleep disorder, mental sleep disorder, insufficient sleep syndrome, drug-related sleep disorder, circadian rhythm sleep disorder. The sleep disorders described in this application may be caused by intrinsic and / or extrinsic factors of the body. In this application, disease-related sleep disorders generally refer to changes in sleep conditions associated with a disease or symptoms of a disease, or situations where drugs used to treat a disease interfere with sleep. Treating a disease may help improve sleep, but sleep disorders may persist after the disease improves. There is a correlation between sleep and central nervous system diseases, especially neurodegenerative diseases. For example, sleep disorders in patients with Alzheimer's disease are associated with changes in sleep structure, including delayed sleep phases, increased number of awakenings at night, reduced time in slow-wave sleep and rapid eye movement sleep, and disrupted stage 2 sleep. Sleep deprivation may activate nonspecific immune parameters and induce a low-level systemic inflammatory state, affect synaptic remodeling, or reduce the clearance of neurotoxic metabolites. Specifically, sleep deprivation may reduce the clearance rate of amyloid protein or alter normal amyloid protein metabolism. In this application, the term "circadian rhythm", also known as "day and night rhythm", generally refers to a physiological phenomenon that is endogenous, continuous, and has regular changes in the mind and body with a cycle of about 24 hours. Circadian rhythm disorders can be caused by endogenous sleep-wake rhythms (biological clocks) and exogenous circadian rhythm disorders (desynchronization). The causes may be endogenous (such as delayed or advanced sleep phase syndrome) or exogenous (such as jet lag, shift work). Circadian rhythm sleep disorders may occur in patients with Alzheimer's disease or Parkinson's disease, as well as patients with head trauma or encephalitis. In this application, the term "sleep-related substances" generally refers to substances that affect sleep or substances that can be used to characterize the sleep state. Sleep-related substances may also include substances related to circadian rhythms. For example, sleep-related substances can regulate the patterns of wakefulness and sleep. For example, sleep-related substances can be produced and / or secreted by the body. Sleep-related substances may include hormones and / or neurotransmitters. Sleep-related substances may include one or more monoamine neurotransmitters. For example, monoamine neurotransmitters may include dopamine, norepinephrine, epinephrine, serotonin, and melatonin. Sleep-related substances may include one or more selected from the following group: melatonin, serotonin, norepinephrine, epinephrine, dopamine, growth hormone, cortisol, thyroid hormone, gonadotropin, sex hormone, insulin, leptin, and / or ghrelin. In this application, the term "comprising" generally means including, encompassing, containing or encompassing. In some cases, it also means "being", "consisting of...". 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 numerical value. Detailed Description of the Invention The applicant unexpectedly discovered that ATP6V1B2 is a potential target for improving sleep, and that proton pump agonists can improve sleep, thereby being used for preventing and / or treating sleep disorders. On the one hand, the present application provides a proton pump regulator capable of regulating ATP6V1B2 and / or its functionally active fragments, and its use in preparing an agent for preventing and / or treating a disease, wherein the disease includes sleep disorders. ATP6V1B2 and its functionally active fragments In the present application, the ATP6V1B2 may be derived from any organism. For example, the ATP6V1B2 may be derived from humans or mice. In the present application, the ATP6V1B2 may comprise the amino acid sequence shown in SEQ ID NO: 8 or 16. In the present application, the functionally active fragment of ATP6V1B2 can be combined with the binding agent described in the present application. In the present application, the functionally active fragment of ATP6V1B2 can have the ability to specifically bind to the amino acid sequence shown in SEQ ID NO: 5. For example, the functionally active fragment of ATP6V1B2 can include a truncation of ATP6V1B2. For example, the functionally active fragment of ATP6V1B2 can include at least a portion of the amino acid sequence from positions 287 to 512 of the human ATP6V1B2 protein. For example, the functionally active fragment of ATP6V1B2 can include at least a portion of the amino acid sequence from positions 287 to 512 of the mouse ATP6V1B2 protein. In the present application, the ATP6V1B2 and / or its functionally active fragment may comprise the amino acid sequence shown in any one of SEQ ID NOs: 8, 10-11, and 16. In the present application, the nucleic acid sequence encoding the ATP6V1B2 and / or its functionally active fragment may include the nucleic acid sequence shown in SEQ ID NO: 9 or 17. In the present application, the activity of ATP6V1B2 can include the biological activity of ATP6V1B2 protein and / or its functionally active fragment (e.g., can include a measurable downstream effect caused by it). For example, the activity of ATP6V1B2 can include increasing the expression level and / or activity of the proton pump-related protein. In the present application, the increase can include increasing the activity of the proton pump-related protein by at least about 10% compared to the activity of the original proton pump-related protein in the subject. For example, it can increase by 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. ATP6V1B2 regulators In the present application, the ATP6V1B2 modulator can bind to ATP6V1B2. For example, the ATP6V1B2 modulator can be a binding agent of ATP6V1B2. In the present application, the binding of the ATP6V1B2 modulator to ATP6V1B2 can be specific. For example, the ATP6V1B2 modulator can be greater than or equal to about 10 5 M -1 (For example, greater than or equal to about 10 5 M -1 , greater than or equal to about 10 6 M -1 , greater than or equal to about 10 7 M -1 , greater than or equal to about 10 8 M -1 , greater than or equal to about 10 9 M -1 , greater than or equal to about 10 10 M -1 , greater than or equal to about 10 11 M -1 , greater than or equal to about 10 12 M -1 , greater than or equal to about 10 13 M -1 or greater) of Ka (i.e., the equilibrium association constant for the binding interaction, which is 1 / M); or, less than or equal to about 10 -5 M (e.g., less than or equal to about 10 -5 M, less than or equal to about 10 -6 M, less than or equal to about 10 -7 M, less than or equal to about 10 -8M, less than or equal to about 10 -9 M, less than or equal to about 10 -10 M, less than or equal to about 10 -11 M, less than or equal to about 10 -12 M, less than or equal to about 10 -13 For example, the binding of the ATP6V1B2 modulator to ATP6V1B2 and / or its functionally active fragment can be in vivo or in vitro. In the present application, the ATP6V1B2 modulator can regulate the expression level and / or activity of a proton pump-related protein. For example, the ATP6V1B2 modulator can increase the expression level and / or activity of a proton pump-related protein. For example, the expression level of the proton pump-related protein includes the expression level of a gene encoding a proton pump-related protein, the transcription level of a gene encoding a proton pump-related protein, and / or the expression level of a proton pump-related protein. For example, the increase includes an increase in the expression level and / or activity of the proton pump-related protein by at least about 10% compared to the expression level and / or activity of the original proton pump-related protein in the subject. In the present application, the increase may include an increase in the expression level of the proton pump-related protein by at least about 5% compared to the expression level of the original proton pump-related protein in the subject. For example, the improvement can be at least about 10%, 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. For example, the expression level of a proton pump-related protein can be measured by conventional techniques in the art. For example, including but not limited to measuring the expression level of a proton pump-related protein by performing an assay selected from the group consisting of: qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. For example, the expression level of a proton pump-related protein can be measured, but not limited to, by utilizing a substance selected from the group consisting of: a primer capable of specifically amplifying a gene encoding a proton pump-related protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-related protein, a nucleic acid molecule that specifically binds to a proton pump-related protein, a small molecule that specifically binds to a proton pump-related protein, a probe that specifically binds to a proton pump-related protein, and a polypeptide that specifically binds to a proton pump-related protein. In the present application, the proton pump-related protein may include NADH dehydrogenase, coenzyme Q, succinate-Coenzyme Q reductase, cytochrome c and / or coenzyme Q-cytochrome c reductase. In the present application, the activity of the proton pump-associated protein may include the biological activity of the proton pump-associated protein. For example, the activity of the proton pump-related protein can be measured by the activity level of the hydrogen / potassium ATPase system (also known as hydrogen / potassium ion ATPase, i.e., H+ / K+ATPase); and / or the activity level of the H2 receptor. For example, the activity of the proton pump-related protein can be measured by its ability to regulate lysosomal acidity. For example, the activity of the proton pump-related protein can be measured by the acidity level of the lysosome. Lysosomal acidity generally refers to the acidic environment inside the lysosome (lysosome) in the cell, which is usually maintained by the proton pump (H+-ATPase) on the lysosomal membrane. The main function of the lysosomal H+-ATPase is to transport protons on one side of the cytoplasm to the lysosomal chamber, thereby maintaining or increasing the acidic environment of the lysosome. ATP6V1B2 participates in the formation of the proton pump, can regulate the activity of the proton pump, and can directly affect the proton (H+ ion) concentration in the lysosome. In the present application, the increase in the activity of the proton pump-associated protein can include an increase in the activity of the proton pump-associated protein by at least about 5% compared to the activity of the original proton pump-associated protein in the subject. For example, the activity can be increased by at least about 10%, 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 the present application, the ATP6V1B2 modulator can modulate the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the ATP6V1B2 modulator can increase the expression level and / or biological activity of ATP6V1B2. In the present application, the increase can include an increase in the expression level of ATP6V1B2 by at least about 10% compared to the original expression level of ATP6V1B2 in the subject. For example, the increase 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. For example, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. For example, the expression level can include the amount of a specific gene (e.g., human ATP6V1B2 gene) polynucleotide, mRNA, or amino acid product or protein. The expression level can include the amount of a specific gene (e.g., human ATP6V1B2 gene) transcribed polynucleotide, translated protein, or post-translationally modified protein fragment. For example, the expression level of ATP6V1B2 can be measured by conventional techniques in the art. For example, this includes, but is not limited to, measuring the expression level of ATP6V1B2 by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. For example, the expression level of ATP6V1B2 can be measured, but is not limited to, using a substance selected from the group consisting of: a primer that specifically amplifies the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein. In the present application, the ATP6V1B2 modulator can improve cognitive ability. For example, the cognitive ability can include cognitive ability that can be measured by a novel object recognition behavioral experiment. For example, the cognitive ability can include cognitive ability that can be measured by a water maze behavioral experiment. For example, the improvement can include that after the ATP6V1B2 modulator is administered to the subject, the subject's cognitive ability is improved. For example, the improvement in the subject's cognitive ability can include that in a water maze behavioral experiment, the subject's time in the quadrant where the platform is located is increased, the interval time to enter the quadrant where the platform is located is reduced, and / or the number of times crossing the quadrant where the platform is located is increased. In the present application, the ATP6V1B2 modulator can increase neuronal synaptic transmitter release. For example, the increase includes an increase of at least about 10% compared to the level of native neuronal synaptic transmitter release in the subject. For example, the increase can be at least about 20%, at least about 50%, 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 the present application, the ATP6V1B2 modulator can increase the firing frequency of excitatory postsynaptic currents. In the present application, the increase includes an increase of at least about 10% compared to the level of the original firing frequency of excitatory postsynaptic currents in the subject. For example, the increase can be at least about 20%, at least about 50%, 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 the present application, the ATP6V1B2 regulator may include a small molecule compound, a polymer and / or a biomacromolecule. In the present application, the ATP6V1B2 regulator may include a protein and / or a polypeptide. In the present application, the ATP6V1B2 modulator may comprise two parts, the first part comprising a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof, and the second part comprising a molecule that delivers the first part. In certain embodiments, the ATP6V1B2 modulator consists of the first part and the second part. In certain embodiments, the ATP6V1B2 modulator comprises at least the first part and the second part. In certain embodiments, the ATP6V1B2 modulator may comprise only a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof. In certain embodiments, the ATP6V1B2 modulator may comprise only the first portion. In certain embodiments, the amino acid sequence of the first portion may comprise the amino acid sequence shown in SEQ ID NO: 85 and / or variants thereof. In certain embodiments, the amino acid sequence of the first portion may comprise at least one mutated amino acid residue compared to the amino acid sequence shown in SEQ ID NO: 85. In certain embodiments, the number of mutated amino acid residues is 1 to 8. For example, the number of mutated amino acid residues is 1, 2, 3, 4, 5, 6, 7 or 8. In certain embodiments, the at least one mutated amino acid residue is at least two mutated amino acid residues. For example, the number of mutated amino acid residues is 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 or 2 to 3. For example, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment comprises 1, 2, 3, 4 or 5 mutated amino acid residues compared to the amino acid sequence shown in SEQ ID NO: 85. In certain embodiments, the first portion may comprise the amino acid sequence set forth in SEQ ID NO: 19 or 99, and / or variants thereof, wherein X is any amino acid. The amino acid sequence set forth in SEQ ID NO: 19 is: XXVDXXC[X-], where X is any amino acid, and wherein amino acid position 8 may be absent. In certain embodiments, the first portion may comprise the amino acid sequence set forth in any one of SEQ ID NOs: 20-30, 93-98, and / or variants thereof, wherein X is any amino acid. The amino acid sequence set forth in SEQ ID NO: 26 is: XXVDXXC[-S], where X is any amino acid, and [-S] indicates that amino acid position 8 may be serine or absent. The amino acid sequence set forth in SEQ ID NO: 28 is: XXVDXXCX, where X is any amino acid. In certain embodiments, the first portion may comprise the amino acid sequence set forth in any one of SEQ ID NOs: 25-30, and / or variants thereof, wherein X is any amino acid. In certain embodiments, the first portion may comprise the amino acid sequence set forth in any one of SEQ ID NOs: 31-41, 86-92, and / or variants thereof. The amino acid sequence set forth in SEQ ID NO: 37 is: [RTS][PWD]VD[GFYV][VTY]C[-S], wherein position 1 may be arginine, threonine, or serine, position 2 may be proline, tryptophan, or aspartic acid, position 5 may be glycine, phenylalanine, tyrosine, or valine, position 6 may be valine, threonine, or tyrosine, and position 8 may be serine or absent. In certain embodiments, the first portion may comprise the amino acid sequence set forth in any one of SEQ ID NOs: 19, 42-48, and / or variants thereof. In certain embodiments, the ATP6V1B2 modulator may comprise a protein and / or a polypeptide. In certain embodiments, the first portion comprises a protein and / or a polypeptide. In certain embodiments, the first portion may be a polypeptide, which may contain cysteine ​​residues. The cysteine ​​residues in the amino acid sequence of the polypeptide may not be modified to block sulfhydryl groups. For example, if the cysteine ​​residues in the amino acid sequence of the polypeptide are blocked by sulfhydryl groups, the polypeptide may lose its ability to bind to the ATP6V1B2 protein. In certain embodiments, the first portion may be a polypeptide, which may contain a serine residue, and the serine residue in the amino acid sequence of the polypeptide is not phosphorylated. For example, if the serine residue in the amino acid sequence of the polypeptide is phosphorylated, it may lose the ability to bind to the ATP6V1B2 protein. In certain embodiments, the first portion can be a multimer. In certain embodiments, the multimer can include a homodimer. In certain embodiments, the second portion is not limited to any form in the present application, and all forms of molecules capable of delivering the first portion are included. In certain embodiments, the second portion may include a modifying group, a small molecule, a nanoparticle, an exosome, a virus, a nucleic acid, a protein, and / or a polypeptide. In the present application, the second part has the function of delivering the first part into cells and / or transporting the first part across the blood-brain barrier to the brain. In certain embodiments, the second part is capable of delivering the first part into cells expressing ATP6V1B2. In the present application, the second portion includes a modification or transformation of the molecule of the first portion so that it can be delivered to a location where it can function. For example, the second portion may include a group that is rationally designed and modified to modify the molecule of the first portion, changing its properties to make it easier to cross the blood-brain barrier and / or enter cells. In certain embodiments, the second portion may include a group for modifying the first portion. In certain embodiments, the second portion may include a group for PEGylation, lipidation, and / or glycosylation of the first portion. In the present application, the first part can be wrapped inside the second part so that it can be delivered to the position where it can play a role. In some embodiments, the second part can include nanoparticles. For example, the second part can include liposomes. In some embodiments, the nanoparticles and / or liposomes can be further modified or transformed to improve the delivery effect of the first part. In some embodiments, the second part can include liposomes, and the liposomes can include modified liposomes, and the modifications include polypeptide modification, antibody modification, glycosyl modification, ligand modification, nucleic acid aptamer and / or multi-target modification. In certain embodiments, the second portion may include a molecule that interferes with the physiological barrier function of the blood-brain barrier and / or a binder to a transporter protein on the blood-brain barrier. In certain embodiments, the interference with the physiological barrier function of the blood-brain barrier may include increasing the permeability of the blood-brain barrier. In certain embodiments, the interference with the physiological barrier function of the blood-brain barrier may include inhibiting the efflux system of the blood-brain barrier. In certain embodiments, the molecule that interferes with the physiological barrier function of the blood-brain barrier includes an efflux inhibitor. In some embodiments, the second part can include a binder for a transporter on the blood-brain barrier to complete the trans-blood-brain barrier delivery of the first part of the molecule by the transporter. In some embodiments, the transporter on the blood-brain barrier can include insulin receptor (IR), transferrin receptor (TfR), low density lipoprotein receptor (LDLR), low density lipoprotein receptor-related protein 1 (LRP1) and LRP2 and / or diphtheria toxin receptor (DTR). In certain embodiments, the binding agent for the transporter on the blood-brain barrier may include a transporter binding protein on the blood-brain barrier. In certain embodiments, the transporter binding protein on the blood-brain barrier may include an antibody and / or an antigen-binding fragment thereof that targets the transporter on the blood-brain barrier. In certain embodiments, the transporter binding protein on the blood-brain barrier may include an antibody and / or an antigen-binding fragment thereof that targets the transferrin receptor. In certain embodiments, the second portion includes a binding agent for a protein that mediates endocytosis, so as to directly or indirectly complete the intracellular delivery of the first portion of molecules via the protein that mediates endocytosis. In certain embodiments, the protein that mediates endocytosis may include a protein and / or polypeptide that directly participates in endocytosis, or may include a protein and / or polypeptide that indirectly participates in endocytosis, as long as the binding agent can deliver the first portion of molecules into the cell. In certain embodiments, the second portion may include a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide may include a cell-penetrating peptide that enters the cell via an endocytic pathway and / or a direct penetration pathway. In certain embodiments, the cell-penetrating peptide may include a cationic cell-penetrating peptide, an amphipathic cell-penetrating peptide, and / or a hydrophobic cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide may include a linear peptide and / or a cyclic peptide. In some embodiments, the second portion may include a cell-penetrating peptide derived from TAT protein. In some embodiments, the second portion may include a variant of a cell-penetrating peptide derived from TAT protein, and the variant may include amino terminal deletion, carboxyl terminal deletion, internal deletion and / or amino acid replacement, and the remaining amino acid sequence generally has the same amino acid as the corresponding position of the amino acid sequence from which it is derived. In some embodiments, the variant generally has at least 60%, 70%, 80%, 90%, or 100% biological activity of the amino acid sequence from which it is derived. In some embodiments, the variant of the cell-penetrating peptide derived from TAT protein, has the function of delivering the first portion to intracellular and / or allowing it to be transported to the brain across the blood-brain barrier. In certain embodiments, the second portion may comprise the amino acid sequence shown in SEQ ID NO: 79 and / or variants thereof. In certain embodiments, the second portion may comprise an amino acid sequence having at least one amino acid deleted at the N-terminus compared to the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the second portion may comprise an amino acid sequence having one to five amino acid deleted at the N-terminus compared to the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the second portion may comprise an amino acid sequence having one, two, three, four, or five amino acid deleted at the N-terminus compared to the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the second portion may comprise the amino acid sequence shown in any one of SEQ ID NOs: 80-84 and / or variants thereof. In some embodiments, the second portion can be connected to the first portion. In some embodiments, the first portion and the second portion are directly or indirectly connected. In some embodiments, the first portion and the second portion can be connected by a peptide bond. In some embodiments, the first portion and the second portion can be connected by a linker. In some embodiments, the first portion and the second portion can be connected by a non-peptide. In certain embodiments, the ATP6V1B2 modulator can be a fusion protein and / or fusion polypeptide. In certain embodiments, the fusion protein and / or fusion polypeptide can include the first portion and the second portion. In certain embodiments, the first portion includes a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof, and the second portion includes a molecule that delivers the first portion, and the first portion and the second portion form a fusion polypeptide. In certain embodiments, the ATP6V1B2 modulator can include a multimer. In certain embodiments, the multimer can include a homodimer. In certain embodiments, the cysteine ​​in the amino acid sequence of the ATP6V1B2 modulator does not have a thiol-blocking modification. In certain embodiments, the serine in the amino acid sequence of the ATP6V1B2 modulator does not have a phosphorylation modification. In certain embodiments, the ATP6V1B2 modulator may comprise an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the ATP6V1B2 modulator may comprise an amino acid sequence as shown in any one of SEQ ID NOs: 72-78, 100-104 and / or variants thereof. In certain embodiments, the ATP6V1B2 modulator may comprise an amino acid sequence as shown in any one of SEQ ID NOs: 1-3 and / or variants thereof. In the present application, the ATP6V1B2 modulator can prevent and / or treat sleep disorders. In certain embodiments, the sleep disorder may include sleep abnormalities. In certain embodiments, the sleep disorder may include insomnia, narcolepsy, sleep apnea, lower limb ataxia, nocturnal myoclonus, recurrent hypersomnia, post-traumatic hypersomnia, delayed sleep phase syndrome, delayed sleep cycle syndrome, and non-24-hour sleep-wake cycle disorders. In certain embodiments, the sleep disorder may include adaptive insomnia, poor sleep habits, psychophysiological insomnia, somatic sleep disorders, mental sleep disorders, insufficient sleep syndrome, drug-related sleep disorders, and / or circadian rhythm sleep disorders. In certain embodiments, the sleep disorder may include sleep disorders associated with cardiovascular diseases and / or neurological diseases. In certain embodiments, the sleep disorder may include sleep disorders associated with stroke, sleep disorders associated with cognitive disorders, and / or sleep disorders associated with neurodegenerative diseases. In certain embodiments, the sleep disorder may include sleep disorders associated with Alzheimer's disease. In the present application, the ATP6V1B2 modulator is capable of regulating circadian rhythm. In the present application, the ATP6V1B2 modulator is capable of regulating wakefulness. In the present application, the ATP6V1B2 regulator can regulate the secretion of sleep-related substances in the body. In certain embodiments, the ATP6V1B2 modulator can regulate the secretion of sleep-related substances in the body, thereby improving the body's sleep state. In certain embodiments, the ATP6V1B2 modulator can increase the production and / or secretion of a substance that helps improve sleep in the body. For example, the ATP6V1B2 modulator can increase the production and / or secretion of melatonin. In the present application, the increase includes an increase of at least about 5% compared to the level of the amount, production capacity, or secretion capacity of the substance that helps improve sleep in the subject before administration of the ATP6V1B2 modulation. For example, the increase can be at least about 10%, at least about 15%, at least about 20%, at least about 50%, 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 certain embodiments, the ATP6V1B2 modulator can reduce the production and / or secretion of substances that are detrimental to sleep in the body. For example, the ATP6V1B2 modulator can reduce the production and / or secretion of cortisol. In the present application, the reduction includes a reduction of at least about 5% compared to the level of the amount, production capacity, or secretion capacity of the substance that is detrimental to sleep in the subject before administration of the ATP6V1B2 modulator. For example, the reduction can be at least about 10%, at least about 15%, at least about 20%, at least about 50%, 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%, or more. In certain embodiments, the ATP6V1B2 modulator can regulate the secretion of sleep-related substances in the body, thereby improving the body's circadian rhythm. In certain embodiments, the ATP6V1B2 modulator can regulate substances related to circadian rhythm in the body, thereby improving the body's regulation of wakefulness and sleep. For example, the ATP6V1B2 modulator can regulate the production and / or secretion of melatonin in the body. In some embodiments, the sleep-related substance may include a hormone and / or a neurotransmitter. In some embodiments, the sleep-related substance may include a monoamine neurotransmitter. In some embodiments, the sleep-related substance may include one or more selected from the group consisting of melatonin, growth hormone, cortisol, serotonin, thyroid hormone, gonadotropin, sex hormone, insulin, leptin, and ghrelin. In the present application, the ATP6V1B2 modulator is capable of regulating the sleep state. In certain embodiments, the ATP6V1B2 modulator can regulate the sleep state of non-rapid eye movement sleep and / or rapid eye movement sleep. In certain embodiments, the ATP6V1B2 modulator can increase the number, time and / or frequency of spindle waves in the sleep state. In certain embodiments, the ATP6V1B2 modulator can increase the number, time and / or frequency of spindle waves in the first sleep cycle. In certain embodiments, the ATP6V1B2 modulator can increase the frequency of rapid eye movement (REM) at the end of the sleep cycle. In certain embodiments, the ATP6V1B2 modulator can increase the frequency of rapid eye movement (REM) at the end of the first sleep cycle. In certain embodiments, the ATP6V1B2 modulator can optimize sleep architecture. For example, the ATP6V1B2 modulator can increase the proportion of NREM (non-rapid eye movement) sleep or increase the time spent in NREM (non-rapid eye movement) sleep. For example, ATP6V1B2 regulation can stabilize the rapid eye movement (REM) cycle and enhance the rhythmicity of the cycle (e.g., 90-minute cyclic fluctuations). In certain embodiments, the ATP6V1B2 modulator can shorten sleep latency. In certain embodiments, the ATP6V1B2 modulator can reduce the number of awakenings and / or reduce the duration of awakenings. In certain embodiments, the ATP6V1B2 modulator can improve physiological indicators during sleep, for example, enhanced respiratory stability during sleep and optimized autonomic nervous system regulation (for example, increased high-frequency power of heart rate variability (HRV)). In certain embodiments, the ATP6V1B2 modulator is capable of improving sleep rhythm characteristics. Subjects In the present application, the subject may include a mammal. For example, the subject may include a rodent and / or a primate, for example, the subject may include a human. In the present application, the subject may be at any age. For example, the subject may be at an elderly stage. In the present application, the subject may include patients with sleep disorders, stroke patients, cognitive impairment patients and / or neurodegenerative disease patients. In the present application, the subject may include a non-sleep disorder patient, a non-stroke patient, a non-cognitive disorder patient, and / or a non-neurodegenerative disease patient. For example, the subject may be a normal person and / or a healthy person. For example, the subject may have a need and / or desire to further improve their learning ability. In the present application, the subject may include patients with sleep disorders and / or patients with damage caused by sleep disorders. In the present application, the subject may also include patients who have symptoms of sleep disorders but have not been diagnosed. For example, the subject may include patients with sleep disorders. For example, the subject may include patients with insomnia, narcolepsy, sleep apnea, lower limb ataxia, nocturnal myoclonus, recurrent hypersomnia, post-traumatic hypersomnia, delayed sleep phase syndrome, delayed sleep cycle syndrome and / or non-24-hour sleep-wake cycle disorders. For example, the subject may include patients with adaptive insomnia, poor sleeping habits, psychophysiological insomnia, somatic sleep disorders, mental sleep disorders, insufficient sleep syndrome, drug-related sleep disorders and / or circadian rhythm sleep disorders. In the present application, the sleep disorder of the subject may be a complication or sequelae of other diseases. For example, the other diseases may include cardiovascular and cerebrovascular diseases, cognitive disorders and / or neurodegenerative diseases. For example, the subject may include patients suffering from cardiovascular and cerebrovascular diseases and sleep disorders at the same time. For example, the subject may include patients suffering from stroke and sleep disorders at the same time. For example, the subject may include patients who develop sleep disorder symptoms after suffering a stroke. For example, the subject may include patients suffering from cognitive disorders and sleep disorders at the same time. For example, the subject may include patients suffering from neurodegenerative diseases and sleep disorders at the same time. For example, the subject may include patients suffering from Alzheimer's disease and sleep disorders at the same time. In the present application, the subject may include a patient with cerebral stroke and / or a patient with damage caused by a stroke. For example, the subject may include a patient with ischemic stroke and / or hemorrhagic stroke. For example, the subject may include a patient with cerebral infarction. For example, the subject may include a patient with lacunar infarction, ischemic infarction, and / or hemorrhagic infarction. For example, the subject may include a patient with thrombosis, embolism, and / or hypotension. For example, the subject may include a patient with atherosclerosis, aneurysms, vascular malformations, arteritis, and / or vasospasm. In the present application, the subject may include a patient with intraparenchymal hemorrhage, intraventricular hemorrhage, and / or subarachnoid hemorrhage. For example, the subject may include a patient with primary cerebral hemorrhage and / or secondary cerebral hemorrhage. For example, the subject may include a patient with aneurysmal subarachnoid hemorrhage. For example, the subject may include a patient with vascular malformations, aneurysms, blood diseases, cerebral amyloid angiopathy, abnormal vascular networks at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy, and / or aneurysmal stroke. In the present application, the subject may also include a patient with damage caused by a stroke. For example, the patient may include patients with observed intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage. For example, the patient may include patients with observed edema, hematoma and / or mass effect. For example, the patient may include patients with observed dense artery sign, island band sign, blurred outline or decreased density of the lenticular nucleus, occlusion of cerebral perforator arterioles, edema and / or mass effect. In the present application, the subject may include a patient with a neurodegenerative disease. For example, the subject may include a patient with Alzheimer's disease. For example, the patient with Alzheimer's disease may be in the early, early, middle, or late stages of Alzheimer's disease. In the present application, the subject may include a patient with cognitive impairment. For example, the subject may have early cognitive impairment (MCI) (e.g., difficulty in losing short-term memory, expressing or understanding abstract things, mood or behavior volatility, difficulty in learning new things and following complex instructions, decreased judgment and / or basic self-care needs to be reminded by others), moderate cognitive impairment (e.g., confusion between long-term memory and reality memory, poor expression, behavioral personality changes or emotional instability and / or the need for others to assist in self-care) or severe cognitive impairment (e.g., memory impairment, physical activity and mental state decline, cannot be effectively expressed or communicated, cannot take care of oneself and / or biological clock confusion). In the present application, the subject may have a disease that can cause the cognitive impairment to be induced. For example, the subject may have Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). Prevent and / or treat disease On the other hand, the present application provides use of the proton pump modulator described herein in the preparation of a reagent for preventing and / or treating a disease, wherein the disease includes sleep disorders. In another aspect, the present application provides a method for preventing and / or treating a disease, comprising administering the proton pump modulator described herein to a subject in need thereof, wherein the disease comprises a sleep disorder. In another aspect, the present application provides use of the proton pump modulator described herein in preventing and / or treating a disease, wherein the disease includes a sleep disorder. The agents described herein can be administered in any manner. For example, the agents described herein can be administered orally and / or by injection. For example, the agents described herein can be formulated into a form suitable for their mode of use. For example, the agents described herein can be formulated into a form suitable for oral administration and / or by injection. The proton pump regulating agent described herein and / or the reagent for preventing and / or treating disease described herein can be administered in a dosage of a therapeutically effective amount. For example, a therapeutically effective amount may include an amount that effectively prevents or improves the symptoms of one or more diseases or conditions or the development of the disease or condition when administered to a subject. For example, a therapeutically effective amount may include an amount of a binding compound sufficient to cause symptom improvement, such as an amount that treats, cures, prevents or improves a related medical condition or increases the speed of treatment, cure, prevention or improvement of such conditions. For example, when an active ingredient administered alone is administered to an individual, a therapeutically effective dose refers only to the ingredient. For example, when administered in combination, a therapeutically effective dose refers to the combined amount of the active ingredients that cause a therapeutic effect, whether in combination, administered sequentially or administered simultaneously. The proton pump modulators described herein can prevent and / or treat sleep disorders. The proton pump modulators described herein can prevent and / or treat damage caused by sleep disorders. In the present application, the preventive and / or therapeutic effect of the ATP6V1B2 modulator for sleep disorders can be evaluated by detection methods known in the art. For example, the preventive and / or therapeutic effect of the ATP6V1B2 modulator for sleep disorders can be evaluated by detecting the sleep state of the subject. For example, the preventive and / or therapeutic effect of the ATP6V1B2 modulator for sleep disorders can be evaluated by polymorphic sleep monitoring. For example, the preventive and / or therapeutic effect of the ATP6V1B2 modulator for sleep disorders can be evaluated by the subject's brain waves. For example, the preventive and / or therapeutic effect of the ATP6V1B2 modulator for sleep disorders can be evaluated by a sleep scale. For example, the preventive and / or therapeutic effect of the ATP6V1B2 modulator for sleep disorders can be evaluated by detecting sleep-related substances. In the present application, the prevention and / or treatment not only includes preventing and / or treating the disease, but also generally includes preventing the onset of the disease, slowing down or reversing the progression of the disease, preventing or slowing down the onset of one or more symptoms associated with the disease, reducing and / or alleviating one or more symptoms associated with the disease, reducing the severity and / or duration of the disease and / or any symptoms associated therewith and / or preventing the disease and / or any symptoms associated therewith from further increasing, preventing, reducing or reversing any physiological damage caused by the disease, and any pharmacological effects that are generally beneficial to the patient being treated. For example, the modulators described herein, the polypeptides described herein, the fusion polypeptides described herein, the immunoconjugates described herein, the nucleic acid molecules described herein, the vectors described herein, the cells described herein, the pharmaceutical compositions described herein and / or the reagents for preventing and / or treating the disease described herein do not need to achieve a complete cure or eradicate any symptoms or manifestations of the disease. As recognized in the relevant art, drugs used as therapeutic agents can reduce the severity of a given disease state, but do not need to eliminate every manifestation of the disease to be considered as useful therapeutic agents. Similarly, a prophylactically administered treatment does not need to be completely effective in preventing the onset of a condition to constitute a viable preventative agent. It is sufficient to simply reduce the effects of the disease in the subject (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood of the disease occurring or worsening. Without intending to be bound by any theory, the following examples are merely intended to illustrate the ATP6V1B2 modulators, preparation methods, and uses of the present invention, and are not intended to limit the scope of the present invention. Example Example 1 Binding of ATP6V1B2 Regulators to ATP6V1B2 and Biological Activity 1.1 Binding of ATP6V1B2 regulators to ATP6V1B2 hATP6V1B2 and different ATP6V1B2 regulator expression plasmids were constructed and simultaneously transfected into HEK 293 cells. Cell proteins were extracted 48 hours after transfection. Protein extraction was performed using Pierce RIPA lysis buffer. For cells grown in a 60 mm dish, 500 μL of Pierce RIPA lysis buffer containing protease inhibitors was added. The cells were harvested using a cell scraper and transferred to a clean 1.5 mL EP tube. After mixing on a rotary mixer at 4°C for 1 hour, the cells were centrifuged at 13,000 rpm for 10 minutes at 4°C to remove cellular debris. Lysates of cells transfected with hATP6V1B2 and other ATP6V1B2 regulators were mixed. 30 μL of the supernatant was added to 10 μL of 4× loading buffer, boiled at 100°C for 5 minutes, and then frozen at -20°C. To the remaining 470 μL of protein lysate, 2 μL of antibody (Anti-GFP, Roche, 11814460001) was added and the mixture was mixed on a rotary mixer at 4°C overnight, for approximately 16-18 hours. 30 μL of Protein G agarose beads (Roche, 11243233001) were placed in an EP tube and washed three times with Pierce RIPA lysis buffer to remove interference from the original stock solution. The protein incubated overnight with the antibody was added to the agarose beads, mixed and incubated at 4°C for 2 hours to allow full binding of the antibody to the protein. The beads were centrifuged at 4000 rpm for 1 minute, the supernatant was aspirated, and 600 μL of Pierce RIPA lysis buffer was added. The beads were gently inverted and centrifuged, and the supernatant was removed. This step was repeated three times to remove nonspecifically bound proteins. Finally, 30 μL of 1× loading buffer was added, mixed, and heated at 60°C for 20 minutes to denature the proteins and store at -20°C. Proteins were analyzed by Western blotting (Myc-Tag (9B11) Mouse mAb, CST, 2276S; Anti-GFP, Roche, 11814460001). The results show that the ATP6V1B2 regulator described in the present application can bind to ATP6V1B2. 1.2 Biological activities of ATP6V1B2 modulators Different ATP6V1B2 modulators were synthesized based on the amino acid information listed in the sequence listing. Two- to three-month-old C57 mice were anesthetized by intraperitoneal injection of 0.1-0.15 ml of 20% ulose. The brain tissue was then rapidly decapitated and placed in an ice-cold mixture of artificial cerebrospinal fluid (ACSF) pre-gassed with 95% O₂ and 5% CO₂ for 2 minutes. The ACSF composition was as follows: 11.7 mM NaCl, 0.36 mM KCl, 0.12 mM NaH₂PO₄, 0.25 mM CaCl₂, 0.12 mM MgCl₂, 25 mM NaHCO₃, and 11 mM glucose. 350 μm coronal hippocampal slices were cut using a vibratome. Hippocampal slices were placed in room temperature ACSF for at least 30 minutes to recover. The slices were then placed in a recording tank and continuously perfused with mixed ACSF at a rate of 2-2.5 ml / min. Under an Olympus BX51 upright microscope, hippocampal CA1 pyramidal neurons were blind-ligated and whole-cell patch clamp recordings were performed using an Axon 700B amplifier and a 1550B digital-to-analog converter. Spontaneous excitatory postsynaptic currents (sEPSCs) of pyramidal neurons were recorded with voltage clamp at a clamp voltage of -70 mV. After recording sEPSCs for 5 minutes, 5 μM of the ATP6V1B2 modulator described herein was administered for 5 minutes, followed by a 10-minute perfusion with ACSF. The recorded data were analyzed using Minianalysis software. The effects of the ATP6V1B2 modulators described herein on spontaneous excitatory post-synaptic currents (sEPSCs) were recorded in hippocampal slices. The results showed that the ATP6V1B2 modulators described herein increased spontaneous excitatory synaptic transmitter release in hippocampal CA1 neurons, primarily by increasing the frequency of excitatory post-synaptic currents, but had no effect on the amplitude of excitatory post-synaptic currents. Example 2 ATP6V1B2 modulators affect the production of sleep-related substances in the body This example illustrates that the ATP6V1B2 modulator described in this application can affect sleep-related substances in the body. Materials and methods Experimental Animals: Nine SPF-grade male C57 mice, aged 3-4 months, were provided by Shanghai Jihui Laboratory Animal Husbandry Co., Ltd. They were acclimated for 14 days in a clean animal room at the Shanghai Advanced Research Institute, with bedding changed weekly. During the experiment, the room temperature was maintained at 20-23°C, the humidity at 40-70%, and the lighting was on for 12 hours daily (8:00 AM to 8:00 PM). C57 mice were randomly divided into PBS, single-dose QD202, and multiple-dose QD202 groups, with 3 mice in each group. The drug was administered orally by gavage around 10:00 AM daily at a dose of 5 mg / kg QD202. Samples were collected 1 hour after the single-dose group and 1 hour after the last oral administration in the multiple-dose group, once daily for 3 consecutive days. Samples were collected 1 hour after the last oral administration in the PBS group after a single oral administration of the corresponding volume of PBS. Sample processing methods were described in the kit instructions. The specific methods are as follows: Plasma: Blood was collected from the heart of anesthetized mice, placed in EDTA anticoagulant tubes, stored on ice, and centrifuged at 4000 × g for 10 minutes at 4°C. The supernatant was collected for analysis. Tissue homogenate: The mouse brain was obtained, and the cortex, hippocampus, striatum, and hypothalamus were sampled on ice. The tissue was rinsed with pre-chilled PBS (0.01 M, pH = 7.4) to remove residual blood. After weighing, the tissue was added with the corresponding volume of PBS containing protease inhibitors (at a weight-to-volume ratio of 1:9). The tissue was thoroughly ground using a tissue grinder and centrifuged at 5000 × g for 5-10 minutes at 4°C. The supernatant was collected for analysis. All samples were diluted 5-fold using the sample diluent provided in the kit for analysis. ELISA Kit Principle: Enzyme-linked immunosorbent assay (ELISA) kits were provided by Wuhan Elabscience Biotechnology Co., Ltd. (Elabscience). Kit Names and Catalog Numbers: Serotonin / 5-hydroxytryptamine (5-HT) ELISA Kit (E-EL-0033c), Norepinephrine ELISA Kit (E-EL-0047c), Mouse Melatonin ELISA Kit (E-EL-M0788c). The kits utilize a competitive ELISA method. Antigen is coated onto an ELISA plate. During the assay, the antigen in the sample (or standard) competes with the coated antigen for binding sites on a biotin-labeled monoclonal antibody, and free components are washed away. Avidin labeled with horseradish peroxidase is added, and biotin specifically binds to the avidin to form an immune complex, and free components are washed away. A chromogenic substrate (TMB) is added, which develops a blue color under the catalysis of horseradish peroxidase and turns yellow upon addition of the stop solution. The OD value was measured at a wavelength of 450 nm using a microplate reader. The antigen concentration was inversely proportional to the OD 450 value. The concentration of the antigen in the sample was calculated by drawing a standard curve. ELISA kit operation steps: refer to the kit instructions, the specific method is as follows: 1. Set up standard wells, blank wells, and sample wells. Add 50 μL of serially diluted standard to the standard wells, 50 μL of standard and sample diluent to the blank wells, and 50 μL of the test sample to the remaining wells. Immediately add 50 μL of biotinylated antibody working solution to each well. Cover the plate with film and incubate at 37°C for 45 minutes. 2. Drain all liquid from the wells and pat dry on clean absorbent paper. Add 350 μL of wash buffer to each well and soak for 1 minute. Aspirate or discard the liquid from the plate and pat dry. Repeat the wash step three times. 3. Add 100 μL of HRP enzyme conjugate working solution to each well, cover the ELISA plate, and incubate at 37°C for 30 minutes. 4. Shake off all liquid in the wells and wash the plate 5 times using the same method as step 2. 5. Add 90 μL of substrate solution (TMB) to each well, cover the ELISA plate, and incubate at 37°C in the dark for 15 minutes. 6. Add 50 μL of stop solution to each well to terminate the reaction. 7. Immediately measure the optical density (OD value) of each well using a microplate reader at a wavelength of 450 nm. 8. Calculate the average OD value of the standard and sample replicates, fit the standard curve of the four-parameter logistic function, and calculate the concentration of the sample to be tested. The results showed that the ATP6V1B2 modulator described in this application can regulate sleep-related substances in the body. One hour after a single dose in the cortex, the concentrations of norepinephrine and serotonin were significantly higher than those in the control group. In the repeated dose group, the concentration of serotonin in the cortex was higher than that in the control group, while the concentration of norepinephrine was no different from that in the control group (Figure 7a, b); The results of plasma detection showed that the concentrations of norepinephrine and serotonin in the repeated dose group were significantly higher than those in the control group, while the concentration of serotonin in the single dose group was no significant difference from that in the control group, while the concentration of norepinephrine in the single dose group was significantly lower than that in the control group (Figure 7c, d). Example 3 ATP6V1B2 modulator improves sleep This example demonstrates that ATP6V1B2 modulators can improve sleep. The effects of administering the ATP6V1B2 modulators of the present application on sleep in mice were evaluated by sleep monitoring, with reference to the experimental method in Oishi, Yo et al. "Polygraphic Recording Procedure for Measuring Sleep in Mice." Journal of visualized experiments: JoVE, 107e53678.25Jan.2016, doi:10.3791 / 53678. Changes in NREM / REM sleep cycles were analyzed using an EEG / EMG synchronous recording system. The specific implementation steps are as follows: 1. Pre-anesthetize the mouse to be operated on using an anesthesia induction box with an oxygen flow rate of 0.5 and an isoflurane concentration of 5%. 2. After deep anesthesia, remove the mouse and fix the upper teeth on the stereotactic injection device. Turn on the knobs for oxygen and isoflurane and adjust the isoflurane concentration to 1.5%. Sterilize surgical tools with 3.75% ethanol, and then apply iodine to the scalp. 4. Use forceps and surgical scissors to cut the mouse scalp along the midline, use cotton swabs to pull the scalp to both sides and tighten the knobs on both sides to fix the mouse head. 5. After fixing the skull, determine the Bregma point and the lambda point, and use a glass needle to level the front and back and left and right to ensure that the z-axis difference is less than 0.05. 6. After leveling, trace the four locations where electrodes need to be implanted on the scalp, namely EEG-PFC (1.5, -1.5), EEG-PTLp (-3, -2.5), and two symmetrical locations on the cerebellum where ground wires need to be implanted. 7. Implant the four copper wires with skull pins prepared in advance into the four locations mentioned above. Apply light-curing glue on the skull pins and use ultraviolet light to harden them. Then apply dental cement on the skull to fix them. 8. Then apply iodine to the back of the mouse to disinfect the skin, and use tweezers and surgical scissors to cut the back skin. 9. Find two symmetrical muscles on the back, implant the tungsten wire ends of the pre-made tungsten wire electrodes into the back muscles, leaving the portion of the insulation burned by the lighter in the muscles. Then use a mixture of 502 and dental powder to fix the tungsten wire ends to ensure that they do not slip out of the muscles. 10. Use a suture needle and suture thread to suture the cut skin on the back. 11. After all electrodes are implanted, insert the plugs of all electrodes into the female connector and record the signal channel information corresponding to the female connector. 12. Finally, use dental cement to seal and fix the socket. 13. Electrical signals can be recorded after the mouse has recovered for at least one week after surgery (Apoll portable neural recording system). 14. Recording began after mice were intraperitoneally injected with dPBS (control group) / the ATP6V1B2 modulator solution described herein (e.g., QD202 at a drug concentration of 0.1 mg / ml and a dose of 2 mg / kg) and then labeled (Arduino software). Data recorded within a time window of up to 12 hours after labeling were analyzed. 15. Import the extracted EEG and EMG signal data into Matlab for analysis. The toolkit can be downloaded from Github. Then, divide the sleep data into three stages: wake, nREM, and REM. This analysis requires reference EEG and EMG signals. Figure 8A shows the EEG and EMG signals corresponding to the three stages. The experimental results are shown in Figures 8B to 8C, where Figure 8B shows the sleep status of the control group, and Figure 8C shows a sleep overview over the 12-hour period after QD202 injection. QD202 injection increased the time spent in NREM sleep in mice. These results demonstrate that the ATP6V1B2 modulators described herein can improve sleep and are useful for treating sleep disorders.

Claims

1. Use of a proton pump regulator capable of regulating ATP6V1B2 and / or a functionally active fragment thereof in the preparation of an agent for preventing and / or treating a disease, wherein the disease includes sleep disorders.

2. The use according to claim 1, wherein the sleep disorder comprises parasomnia.

3. The method according to any one of claims 1 to 2, wherein the sleep disorder comprises insomnia, narcolepsy, sleep apnea, lower limb ataxia, nocturnal myoclonus, recurrent hypersomnia, post-traumatic hypersomnia, delayed sleep phase syndrome, delayed sleep cycle syndrome and non-24-hour sleep-wake cycle disorder.

4. The method according to any one of claims 1 to 2, wherein the sleep disorder comprises adaptive insomnia, poor sleep habits, psychophysiological insomnia, somatic sleep disorder, mental sleep disorder, insufficient sleep syndrome, drug-related sleep disorder and / or circadian rhythm sleep disorder.

5. The use according to any one of claims 1 to 4, wherein the sleep disorder comprises a sleep disorder associated with cardiovascular disease and / or nervous system disease.

6. The use according to any one of claims 1 to 5, wherein the sleep disorder comprises a sleep disorder associated with stroke, a sleep disorder associated with cognitive impairment, and / or a sleep disorder associated with a neurodegenerative disease.

7. The use according to any one of claims 1 to 6, wherein the proton pump modulator is capable of regulating circadian rhythm.

8. The use according to any one of claims 1 to 7, wherein the proton pump modulator is capable of regulating wakefulness.

9. The use according to any one of claims 1 to 8, wherein the proton pump regulator is capable of regulating sleep-related substances in the body.

10. The use according to claim 9, wherein the sleep-related substances include hormones and / or neurotransmitters. The use according to claim 10 , wherein the sleep-related substance comprises monoamine neurotransmitters.

12. The use according to any one of claims 9 to 11, wherein the sleep-related substances comprise one or more selected from the group consisting of melatonin, serotonin, norepinephrine, epinephrine, dopamine, growth hormone, cortisol, thyroid hormone, gonadotropin, sex hormone, insulin, leptin and / or ghrelin.

13. The use according to any one of claims 1 to 12, wherein the proton pump modulator is capable of regulating sleep state.

14. The use according to any one of claims 1 to 13, wherein the proton pump modulator is capable of modulating the sleep state of non-rapid eye movement sleep and / or rapid eye movement sleep.

15. The use according to any one of claims 1 to 14, wherein the proton pump modulator can increase the number, duration and / or frequency of spindle waves during sleep.

16. The use according to any one of claims 1 to 15, wherein the proton pump regulator can increase the number, duration and / or frequency of spindle waves in the first sleep cycle.

17. The use according to any one of claims 1 to 16, wherein the proton pump modulator is capable of increasing the frequency of rapid eye movement (REM) at the end of the sleep cycle.

18. The use according to any one of claims 1 to 17, wherein the proton pump modulator is capable of increasing the frequency of rapid eye movement (REM) at the end of the first sleep cycle.

19. The use according to any one of claims 1 to 18, wherein the ATP6V1B2 and / or functionally active fragments thereof are derived from mammals.

20. The use according to any one of claims 1 to 19, wherein the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse.

21. The use according to any one of claims 1 to 20, wherein the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16.

22. The use according to any one of claims 1 to 21, wherein the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:

5.

23. The use according to any one of claims 1 to 22, wherein the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:

1.

24. The use according to any one of claims 1 to 23, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein.

25. The use according to any one of claims 1 to 24, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein.

26. The use according to any one of claims 1-25, wherein the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11.

27. The use according to any one of claims 1 to 26, wherein the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 9 or 17.

28. The use according to any one of claims 1 to 27, wherein the proton pump modulator is capable of modulating proton pump activity and / or function.

29. The use according to any one of claims 1 to 28, wherein the proton pump modulator can increase the expression level and / or activity of a proton pump-related protein in a subject.

30. The use according to any one of claims 1 to 29, wherein the proton pump modulator is capable of modulating the expression level and / or activity of ATP6V1B2.

31. The use according to any one of claims 1-30, wherein the proton pump modulator is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject, wherein the increase comprises an increase in the expression level and / or activity of ATP6V1B2 by at least about 10% compared to the original expression level and / or activity of ATP6V1B2 in the subject.

32. The use according to any one of claims 30-31, wherein the expression level of ATP6V1B2 comprises the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein.

33. The use of any one of claims 1-32, wherein the proton pump modulator is capable of increasing neuronal synaptic transmitter release, said increase comprising an increase of at least about 10% compared to the level of native neuronal synaptic transmitter release in the subject.

34. The use of any one of claims 1-33, wherein the proton pump modulator increases the firing frequency of excitatory postsynaptic currents, said increase comprising an increase of at least about 10% compared to the level of native firing frequency of excitatory postsynaptic currents in the subject.

35. The use according to any one of claims 1 to 34, wherein the proton pump modulator comprises a protein and / or a polypeptide.

36. The use according to any one of claims 1 to 35, wherein the proton pump modulator comprises the amino acid sequence shown in SEQ ID NO: 19 or 99 and / or variants thereof, wherein X is any amino acid.

37. The use according to any one of claims 1-36, wherein the proton pump modulator comprises an amino acid sequence shown in any one of SEQ ID NOs: 20-30, 93-98 and / or variants thereof, wherein X is any amino acid.

38. The use according to any one of claims 1-37, wherein the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid.

39. The use according to any one of claims 1 to 38, wherein the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 31 to 41, 86 to 92 and / or variants thereof.

40. The use according to any one of claims 1-39, wherein the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 19, 42-48 and / or variants thereof.

41. The use according to any one of claims 1-40, wherein the proton pump modulator comprises a fusion protein and / or a fusion polypeptide.

42. The use according to any one of claims 41, wherein the fusion protein and / or fusion polypeptide comprises a molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing cell membranes.

43. The use according to claim 42, wherein the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing a cell membrane comprises a polypeptide.

44. The use according to any one of claims 42-43, wherein the molecule capable of being transported to the brain across the blood-brain barrier and / or the molecule capable of crossing a cell membrane comprises a cell-penetrating peptide.

45. The use according to claim 44, wherein the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79-84 and / or variants thereof.

46. ​​The use according to any one of claims 1-45, wherein the proton pump modulator comprises an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or variants thereof, wherein X is any amino acid.

47. The use according to any one of claims 1-46, wherein the proton pump modulator comprises an amino acid sequence as shown in any one of SEQ ID NOs: 72-78, 100-104 and / or variants thereof.

48. The use according to any one of claims 1-47, wherein the proton pump modulator comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-3 and / or variants thereof.

49. The use of any one of claims 1-48, wherein the proton pump modulator comprises a multimer.

50. The use of claim 49, wherein the multimer comprises a homodimer.

51. The use according to any one of claims 1 to 50, wherein the cysteine ​​in the amino acid sequence of the proton pump modulator does not have a sulfhydryl blocking modification.

52. The use according to any one of claims 1-51, wherein the serine in the amino acid sequence of the proton pump modulator does not have a phosphorylation modification.

53. The use of any one of claims 1-52, wherein the subject comprises a mammal.

54. The use of any one of claims 1-53, wherein the subject comprises a human.

55. The use according to any one of claims 1 to 54, wherein the agent is formulated for oral administration and / or injection.

56. A proton pump regulator, which regulates ATP6V1B2 and / or a functionally active fragment thereof, for use in preventing and / or treating sleep disorders.

57. A method for preventing and / or treating sleep disorders, comprising administering an effective amount of a proton pump regulator to a subject in need thereof.

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