Disease Model Development and Phenotyping Project

疾病模型开发和表型分析项目

• 批准号: 10592223
• 负责人: Kim Green
• 金额: $ 561.8万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592223
• 关键词: 3xTg-AD mouse; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Animal Model; Award; Behavior; Behavioral; Biological Markers; Brain; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Communities; Data; Data Set; Deposition; Development; Disease model; Electrophysiology (science); Foundations; Funding; Gene Expression; Gene Expression Profiling; Generations; Genetic; Genetic Variation; Genome; Genomics; Goals; Human; Image; International; Investigation; Knock-in; Knock-in Mouse; Knowledge; Knowledge Portal; Late Onset Alzheimer Disease; Literature; Longevity; Medicine; Modeling; Mouse Strains; Mus; Names; Nomenclature; Pathology; Phase; Phenocopy; Phenotype; Physiology; Process; Proteomics; Research; Research Personnel; Resolution; Resources; Risk; Series; Synapses; TREM2 gene; Testing; Therapeutic Intervention; Tissues; Variant; aged; analysis pipeline; assisted reproduction; base; cognitive testing; cohort; density; design; dietary control; disorder subtype; gene replacement; genetic variant; genome wide association study; human model; human tissue; metabolome; metabolomics; microbiome; model development; mouse model; neuroimaging; novel; open data; programs; response; risk variant; screening; single-cell RNA sequencing; tau Proteins; transcriptomics; web site; western diet

ABSTRACT The goal of the Disease Model Development and Phenotyping Project (DMP) is to develop novel mouse models of late-onset Alzheimer’s disease (LOAD), to deeply phenotype these models, and to make all data and mouse strains available to enable researchers to select the optimal mouse model and timepoints for therapeutic and intervention testing, as well as for the testing of hypotheses concerning mechanisms of LOAD. During the past five years, we have generated and deeply phenotyped mice with one component of our base genetic platform in which the Aß region of the App gene was humanized, and we have recently introduced the second component, a humanized MAPT (TAU) locus produced via gene-replacement. We have also used CRISPR and genome replacement to model and validate nine GWAS identified LOAD risk-variants and have analyzed mice with each variant both on a wild-type and 5xFAD background to determine their effects on plaque generation and damage exerted on the brain in response to pathology. In this continuation, we will use the results of these analyses, plus input from the FGBDMC and the literature, to identify combinations of LOAD risk variants most likely to phenocopy LOAD and introduce them on two complementary hAb-KI, hTAU, hAPOE4 platform lines, designed to mimic sub-types of AD that have been recently defined. These models will be characterized across their lifespans to evaluate the effects of variants on the development of pathologies and subsequent tissue damage in combination with aging. The UCI MODEL-AD group utilizes a comprehensive approach to evaluate these LOAD mouse models, which includes behavioral/cognitive assessment, electrophysiological analysis, super- resolution synaptic imaging, neuroimaging, bulk and single-cell RNA-seq, single cell level spatial transcriptomic analysis, proteomics, and microbiome and metabolome investigations including screening for novel biofluid markers associated with progression to LOAD. UCI MODEL-AD will leverage the resources of our NIA-funded Alzheimer’s Disease Research Center combined with the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP-AD) and other human AD datasets to facilitate alignment of data obtained from these mouse models to the human condition to identify the best mouse models for use by the international AD research community. All data and models will be made available without restrictions, via The Jackson Labs (JAX), and data will be explorable via the modeladexplorer.org website, and raw data freely available for download via the AD Knowledge Portal.

抽象的 疾病模型开发和表型项目 (DMP) 的目标是开发新型小鼠模型 迟发性阿尔茨海默氏病 (LOAD) 的研究，深入分析这些模型的表型，并制作所有数据和小鼠模型 可用的菌株使研究人员能够选择最佳的小鼠模型和治疗和治疗的时间点 干预测试，以及有关 LOAD 机制的假设测试。过去期间 五年来，我们已经生成了小鼠并对其进行了深度表型分析，其具有我们基础遗传平台的一个组成部分 其中App基因的Aß区域被人源化，我们最近引入了第二个组件， 通过基因替换产生的人源化 MAPT (TAU) 基因座。我们还使用了 CRISPR 和基因组 替换模型并验证九个 GWAS 确定的 LOAD 风险变异，并分析了每种变异的小鼠 野生型和 5xFAD 背景上的变体，以确定它们对斑块生成和损伤的影响 作用于大脑以响应病理学。在本篇文章中，我们将使用这些分析的结果，再加上 来自 FGBDMC 和文献的输入，以确定最有可能的 LOAD 风险变体组合 phenocopy LOAD 并将它们引入两个互补的 hAb-KI、hTAU、hAPOE4 平台系列，设计 模仿最近定义的 AD 子类型。这些模型的特点是 寿命来评估变异对病理发展和随后的组织损伤的影响 与衰老相结合。 UCI MODEL-AD 小组利用综合方法来评估这些 LOAD 小鼠模型，包括行为/认知评估、电生理分析、超 分辨率突触成像、神经成像、批量和单细胞 RNA-seq、单细胞水平空间转录组 分析、蛋白质组学、微生物组和代谢组研究，包括筛选新型生物流体 与 LOAD 进展相关的标记。 UCI MODEL-AD 将利用我们 NIA 资助的资源 阿尔茨海默病研究中心与加速药物合作伙伴计划相结合 阿尔茨海默氏病 (AMP-AD) 和其他人类 AD 数据集，以促进从这些数据中获得的数据的对齐 根据人类状况建立小鼠模型，以确定供国际 AD 研究使用的最佳小鼠模型 社区。所有数据和模型将通过杰克逊实验室（JAX）无限制地提供，并且 数据可通过 modeladexplorer.org 网站进行探索，原始数据可通过以下网站免费下载： AD知识门户。