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
• 负责人: MICHAEL D KOOB
• 金额: $ 414.73万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525102
• 关键词: Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Animals; Biological Markers; Catalogs; Collaborations; Communities; DNA Resequencing; DNA Sequence; Disease; Disease Progression; Disease susceptibility; Early Onset Familial Alzheimer' s Disease; Etiology; Evaluation; Exhibits; Functional disorder; Gene Cluster; General Population; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Transcription; Genetic study; Genomic DNA; Genomic Segment; Genomics; Goals; Haplotypes; Human; Human Genetics; Link; MAPT gene; Minnesota; Modeling; Molecular; Molecular Disease; Molecular Probes; Mus; Mutation; Orthologous Gene; Pathogenicity; Patients; Phenotype; Play; Proteins; Public Health; Quality Control; RNA; Research; Risk; Role; SNCA gene; Staging; System; TREM2 gene; Technology; Testing; Therapeutic Intervention; Universities; Validation; Variant; Work; base; effective therapy; endophenotype; familial Alzheimer disease; gene interaction; gene product; gene replacement; genetic variant; genome sequencing; genome wide association study; humanized mouse; insight; interest; mouse genome; mouse model; novel; presenilin-1; presenilin-2; protein expression; rare variant; risk variant; success; synuclein; therapeutic evaluation; therapeutic target; tool; transcriptome sequencing; whole genome

This application is proposing to continue and expand the collaboration between the Koob lab at the University of Minnesota and the MODEL-AD Center. We have developed Gene Replacement (GR) approaches that allow us to replace mouse genes with their full human orthologue alleles. The GR targets for this project include many of the human genes most central to the etiology of AD, including APP, PSEN1, PSEN2, and MAPT, as well as genes that play pivotal roles in modulating AD risk, including the APOE gene cluster, the TREM2 gene cluster, the critical region of the MS4A gene cluster, and INPP5D. A set of models will be generated for each GR target genomic region, consisting of a control line with a wt human genomic sequence, and at least one matching line with either a pathogenic mutation or risk variant in that same human genomic sequence. Basic QC evaluations of each GR allele will be performed at the University of Minnesota, and MODEL-AD will then validate them by confirming that each variant line exhibits the expected AD-related endophenotypes. The human alleles that pass the QC and endophenotype validations will then be incorporated into base AD models with additional AD alleles, with the ultimate goal of recreating the human genetics and pathophysiology of AD as closely as is possible in a mouse. JAX will distribute all mouse lines generated by this project without restrictions.

该应用程序建议继续并扩大Koob实验室与 明尼苏达大学和模型广告中心。我们开发了基因替代技术 (GR)这些方法允许我们用完整的人类直系同源等位基因替换小鼠基因。 该项目的GR靶点包括许多对糖尿病的病因学最重要的人类基因。 AD，包括APP、PSEN 1、PSEN 2和MAPT，以及在AD中起关键作用的基因。 调节AD风险，包括APOE基因簇，TREM 2基因簇，关键区域 MS 4A基因簇和INPP 5D。将为每个GR目标生成一组模型 基因组区域，由具有野生型人基因组序列的对照系和至少一个 在同一人类基因组中具有致病性突变或风险变体的匹配系 顺序每个GR等位基因的基本QC评价将在University of 明尼苏达州，然后MODEL-AD将通过确认每个变异系表现出 预期的AD相关内表型。通过QC的人类等位基因， 然后，将内在表型验证纳入基础AD模型， 等位基因，最终目标是重建AD的人类遗传学和病理生理学， 尽可能接近老鼠。JAX将分发这个项目生成的所有鼠标线 不受任何限制。