Matched sets of full human gene-replacement mouse lines for MODEL-AD
用于 MODEL-AD 的全人类基因替换小鼠系的匹配组
基本信息
- 批准号:10468368
- 负责人:
- 金额:$ 132.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesAlzheimer&aposs disease related dementiaAmyloid beta-ProteinAnimal ModelArchivesBrainCodeCollaborationsCommunitiesDNA SequenceDevelopmentEnsureEtiologyEvaluationFunctional disorderGene ClusterGenesGenetic TranscriptionGenomic DNAGenomicsGoalsHaplotypesHomologous GeneHumanImmunohistochemistryMAPT geneMethodsMinnesotaModelingMolecularMolecular DiseaseMusMutationNucleic Acid Regulatory SequencesOrthologous GenePathogenicityPatientsPhenotypeProcessPromoter RegionsProteinsPublic HealthRNARNA SplicingResearchResearch PersonnelRiskShipsTechniquesTechnologyTherapeuticTherapeutic AgentsTissuesUniversitiesUntranslated RNAVariantbasecohortdesigneffective therapyfrailtygene productgene replacementgenetic risk factorimplementation designmouse modelnext generationrisk varianttau Proteinstherapeutic targettooltranscriptome
项目摘要
We are responding to NOT-AG-18-049 “Collaborative Studies on AD/ADRD” by establishing a collaborative effort to
significantly expand the modeling capacity of the MODEL-AD Center. MODEL-AD was established by the NIA to
create, rigorously characterize and ensure the rapid distribution of the next generation of animal models of Late
Onset AD. Critical barriers to progress in making these next generation models are technique limitations that have
put restrictions on the size of the human genomic context incorporated into each of the new modified alleles in the
MODEL-AD mouse lines. Our group at the University of Minnesota (UMN) has developed Gene Replacement (GR)
technologies that allow us to routinely replace mouse genes with their full human orthologs up to several hundred kb
in size. We used this technology to generate a matched set of Microtubule Associated Protein Tau Gene-
Replacement (MAPT-GR) lines of mice in which we replaced the full mouse Mapt genomic coding and regulatory
region (156,547bp) with full human MAPT genomic sequences (190,081bp). We have confirmed that mice
homozygous for this MAPT-GR allele express human tau at endogenous levels, and that all expected splice variants
are found in the appropriate tissues and in ratios expected for the fully functional human MAPT gene. This model set
now includes two wt control lines (H1 or H2 MAPT haplotype) and a growing number of experimental lines that
precisely match the H1 wt control line except for the pathogenic variant that we specifically introduce into that
haplotype. The first of these lines are currently being further characterized by MODEL-AD and are now available to
the AD research community without restriction (JAX). Our specific aims for this collaboration are to: 1. Generate
Gene-Replacement (GR) sets of mouse lines in which genes involved in the etiology of AD have been
replaced by their full human homologs. We are proposing to develop 10 model sets for this collaboration (>20
total lines). 2. Characterize matched sets of GR lines using the established MODEL-AD methods and
distribute without restriction. The most translationally relevant alleles will be incorporated into the current
MODEL-AD “base model”. These GR lines will allow us and other AD researchers to evaluate the molecular impact
of pathogenic mutations and risk variants within the context of the full human gene sequence in which they occur in
patients. These mouse lines will contain all potential human therapeutic targets for each gene, ranging from the full
genomic DNA sequences to all RNA transcription and protein products that they encode. Because the genomic
sequences of these matched sets will differ only at sequences specifically changed in each line, any significant
molecular differences between these lines can confidently be attributed to the risk variant in the experimental lines,
and any therapeutic agents found to effectively correct these dysfunctions could be expected to have direct
therapeutic value to patients.
我们正在响应NOT-AG-18-049“AD/ADRD的合作研究”,通过建立一个合作努力
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MICHAEL D KOOB其他文献
MICHAEL D KOOB的其他文献
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{{ truncateString('MICHAEL D KOOB', 18)}}的其他基金
Single-cell transcriptomic and epigenomic analysis of brain cell vulnerabilities to tauopathies in early AD impacted brain regions
早期 AD 影响大脑区域脑细胞对 tau 蛋白病变脆弱性的单细胞转录组和表观基因组分析
- 批准号:
10667016 - 财政年份:2023
- 资助金额:
$ 132.92万 - 项目类别:
Full human gene replacement mouse models of Alzheimer's Disease
全人类基因替代阿尔茨海默病小鼠模型
- 批准号:
10525102 - 财政年份:2022
- 资助金额:
$ 132.92万 - 项目类别:
Mouse model of human diseases caused by mtDNA mutations
mtDNA突变引起的人类疾病的小鼠模型
- 批准号:
7140342 - 财政年份:2005
- 资助金额:
$ 132.92万 - 项目类别:
Mouse model of human diseases caused by mtDNA mutations
mtDNA突变引起的人类疾病的小鼠模型
- 批准号:
6962761 - 财政年份:2005
- 资助金额:
$ 132.92万 - 项目类别:
Molecular analysis of the genes involved in SCA8 ataxia
SCA8 共济失调相关基因的分子分析
- 批准号:
6529952 - 财政年份:2001
- 资助金额:
$ 132.92万 - 项目类别:
Molecular analysis of the genes involved in SCA8 ataxia
SCA8 共济失调相关基因的分子分析
- 批准号:
6361781 - 财政年份:2001
- 资助金额:
$ 132.92万 - 项目类别:
Molecular analysis of the genes involved in SCA8 ataxia
SCA8 共济失调相关基因的分子分析
- 批准号:
6637375 - 财政年份:2001
- 资助金额:
$ 132.92万 - 项目类别:
Molecular analysis of the genes involved in SCA8 ataxia
SCA8 共济失调相关基因的分子分析
- 批准号:
6928589 - 财政年份:2001
- 资助金额:
$ 132.92万 - 项目类别:
Molecular analysis of the genes involved in SCA8 ataxia
SCA8 共济失调相关基因的分子分析
- 批准号:
6784132 - 财政年份:2001
- 资助金额:
$ 132.92万 - 项目类别:














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