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）的目的是开发新型鼠标模型 晚期晚期阿尔茨海默氏病（负载），以深层表型，并制作所有数据和鼠标 可用于使研究人员可以选择最佳的小鼠模型和时间点的菌株，以进行治疗和 干预测试以及有关负载机制的假设的测试。在过去 五年，我们在基本遗传平台的一个成分中生成并深入表型小鼠 App基因的Aß区域是人性化的，我们最近引入了第二部分， 通过基因替代产生的人源化MAPT（TAU）基因座。我们还使用了CRISPR和基因组 更换建模并验证9个GWAS确定了负载风险变化，并已分析了小鼠 在野生型和5xFAD背景上的变体，以确定它们对斑块产生和损害的影响 响应病理学而施加在大脑上。在此延续中，我们将使用这些分析的结果以及 FGBDMC和文献的输入，以识别最有可能的负载风险变体的组合 近距离载荷并将其引入两个完整的HAB-KI，HTAU，HAPOE4平台线条，设计 对于最近定义的AD的模拟亚型。这些模型将在他们的 寿命以评估变体对病理发展和随后组织损伤的影响 结合衰老。 UCI Model-AD组利用一种全面的方法来评估这些方法 负载小鼠模型，包括行为/认知评估，电生理分析，超级生理分析 分辨率突触成像，神经影像学，散装和单细胞RNA-seq，单细胞水平空间转录组 分析，蛋白质组学以及微生物组和代谢组研究，包括筛查新型生物流体 与加载进展相关的标记。 UCI Model-AD将利用NIA资助的资源 阿尔茨海默氏病研究中心与加速药物合作计划相结合 阿尔茨海默氏病（AMP-AD）和其他人类广告数据集，以促进从这些数据中获得的数据 鼠标模型达到人类状况，以识别国际广告研究的最佳鼠标模型 社区。所有数据和模型将通过杰克逊实验室（JAX）和 数据将可以通过modeladexplorer.org网站进行探索，并且可免费下载的原始数据可通过 广告知识门户。