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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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&apos 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

项目摘要

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.

该应用程序提议继续并扩展KOOB实验室之间的协作明尼苏达大学和模型中心。我们已经开发了基因替代品（GR）使我们能够用其完整的人类直系同源物代替小鼠基因的方法。该项目的GR靶标包括许多人类基因最重要的人类基因 AD，包括App，PSEN1，PSEN2和MAPT，以及在中扮演关键角色的基因调节广告风险，包括APOE基因簇，TREM2基因簇，临界区域 MS4A基因簇和INPP5D每个GR目标将生成一组模型基因组区域，由具有WT人类基因组序列的控制线组成，至少一个在同一人类基因组中，与致病突变或风险变异的匹配线顺序。每个GR等位基因的基本QC评估将在大学进行然后，明尼苏达州和AD模型将通过确认每个变体线展示预期的与广告相关的内型型。通过QC的人类等位基因然后，将与其他广告合并到基本广告模型中等位基因，其最终目标是重现AD的人类遗传学和病理生理学在鼠标中尽可能接近。 JAX将分发该项目生成的所有鼠标线没有限制。