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Construction method and application of IL1R1 gene-humanized modified non-human animal

A technology of non-human animals and construction methods, applied in the fields of plant genetic improvement, botanical equipment and methods, biochemical equipment and methods, etc., capable of solving problems such as genetic complexity

Active Publication Date: 2020-10-20
BIOCYTOGEN PHARMACEUTICALS (BEIJING) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the differences in physiology and pathology between animals and humans, coupled with the complexity of genes, how to construct an "effective" humanized animal model for new drug development is still the biggest challenge

Method used

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  • Construction method and application of IL1R1 gene-humanized modified non-human animal
  • Construction method and application of IL1R1 gene-humanized modified non-human animal
  • Construction method and application of IL1R1 gene-humanized modified non-human animal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0144] Example 1 IL1R1 Gene Humanized Mice

[0145] In this example, a non-human animal (such as a mouse) is modified so that the non-human animal contains a nucleotide sequence encoding a humanized IL1R1 protein, and a genetically modified non-human animal capable of expressing a humanized IL1R1 protein is obtained. . Mouse IL1R1 gene (NCBI Gene ID: 16177, Primary source: MGI: 96545, UniProt: P13504, located at positions 40222480 to 40316201 of chromosome 1 NC_000067.6, based on the transcript NM_008362.2 and its encoded protein NP_032388.1 ( SEQ ID NO.1)) and human IL1R1 gene (NCBI Gene ID: 3554, Primary source: HGNC: 5993, UniProt ID: P14778, located at positions 102069638 to 102179874 of chromosome 2 NC_000002.12, based on transcript NM_000877.4 The comparison diagram of its encoded protein NP_000868.1 (SEQ ID NO.2)) is shown in figure 1 shown.

[0146] In order to achieve the purpose of the present invention, a nucleotide sequence (DNA sequence, cDNA sequence, etc.) en...

Embodiment 2

[0173] Example 2 Preparation of double humanized or multiple double humanized mice

[0174] Double-humanized or multiple-humanized mouse models can also be prepared by using the method or the prepared IL1R1 gene humanized mice. For example, in the aforementioned Example 1, the embryonic stem cells used in the microinjection of blastocysts can be selected from mice containing other genetic modifications such as CD3, PD-1, PD-L1, IL-1β, ST2, or can also be used in On the basis of IL1R1 gene humanized mice, using the isolation of mouse ES embryonic stem cells and gene recombination targeting technology, a mouse model of IL1R1 and other genetic modifications with double genes or multiple genes is obtained. The homozygous or heterozygous IL1R1 mice obtained by this method can also be mated with other genetically modified homozygous or heterozygous mice, and their offspring can be screened. According to Mendelian inheritance, there is a certain probability of obtaining humanized IL1...

Embodiment 3

[0175] Example 3 In vivo drug efficacy verification in animal models

[0176] The IL1R1 gene humanized mice disclosed in the present invention can be used to induce and prepare a variety of human disease models, including asthma, allergy and other models, for testing the in vivo drug efficacy of human specific antibodies. Taking the asthma model as an example, the IL1R1 gene humanized mice prepared by the present invention were selected and sensitized by intraperitoneal injection of ovalbumin (OVA) combined with aluminum hydroxide for 3 times, and 3 weeks after the first injection, 2% OVA was continuously nebulized for 5 days The asthma model can be induced by provocation, the control group replaced OVA with PBS, and the samples were obtained on the 26th day for analysis. The successful establishment of the model was evaluated by detecting serum IgE levels and eosinophils in bronchoalveolar lavage fluid (BALF). Anti-human IL1R1 antibody was used for treatment. At the end of t...

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Abstract

The invention provides a construction method of an IL1R1 gene-humanized modified non-human animal, a humanized IL1R1 protein, a humanized IL1R1 gene, a targeting vector of the IL1R1 gene and application of the targeting vector in the field of biological medicine. By utilizing a homologous recombination manner, a part of nucleotide sequences for encoding human IL1R1 protein are introduced into a non-human animal genome. The humanized IL1R1 protein can be normally expressed in a non-human animal body, and the non-human animal can be used for researching a human IL1R1 signal mechanism and screening drugs for cardiovascular diseases, autoimmune diseases, infectious diseases, degenerative diseases, sleep diseases, tumors or inflammation-related diseases, and has important application value forresearch and development of new drugs of immune targets.

Description

technical field [0001] The invention belongs to the field of animal genetic engineering and genetic modification, and in particular relates to a method for constructing IL1R1 genetically modified non-human animals and its application in the field of biomedicine. Background technique [0002] IL1R1, interleukin receptor type I, also known as CD121a, is a member of the interleukin 1 (IL1) receptor family. IL1 affects almost all cells and organs, and is the main pathogenic factor of inflammatory response, autoimmune response, infectious disease and degenerative disease. Members of the IL1 subfamily include interleukin 1α (IL1α), interleukin 1β (IL1β), and IL1 receptor antagonist (IL1Ra), whose receptors are IL1R1 and interleukin 1 receptor type II (IL1R2). IL1R1 is a functional receptor of the IL1 subfamily, which is responsible for signal transduction, while IL1R2 belongs to the decoy receptor, which does not conduct signals after binding with ligands. When IL1α, IL1β, IL1Ra...

Claims

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Application Information

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IPC IPC(8): C12N15/85A01K67/027C07K14/715C12N15/12A61K49/00
CPCA01K67/0278A01K2207/15A01K2217/072A01K2227/105A01K2267/01A01K2267/03A01K2267/0393A61K49/0008C07K14/7155C12N15/8509C12N2800/107G01N33/6854G01N2333/7155
Inventor 沈月雷姚佳维郭雅南白阳周小飞
Owner BIOCYTOGEN PHARMACEUTICALS (BEIJING) CO LTD
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