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.

摘要 疾病模型开发和表型分型项目的目标是开发新的小鼠模型 晚发性阿尔茨海默病（LOAD），深入表型这些模型，并使所有数据和小鼠 可供研究人员选择的最佳小鼠模型和治疗时间点， 干预测试，以及有关LOAD机制的假设测试。在过去 五年来，我们已经用我们基础遗传平台的一个组成部分产生了小鼠，并对其进行了深入的表型分析， 其中App基因的A12区是人源化的，我们最近引入了第二个组分， 通过基因置换产生的人源化MAPT（TAU）基因座。我们还使用了CRISPR和基因组 替代模型和验证九个GWAS确定的LOAD风险变体，并分析了小鼠与每个 在野生型和5xFAD背景下测定它们对斑块生成和损伤的影响 对大脑的病理反应。在本续中，我们将使用这些分析的结果，加上 FGBDMC和文献的输入，以识别最有可能 表型复制LOAD，并将它们引入两个互补的hAb-KI，hTAU，hAPOE 4平台线，设计 来模拟最近定义的AD亚型。这些模型将在其 寿命，以评价变异体对病理学发展和后续组织损伤的影响 再加上老化。UCI MODEL-AD小组利用综合方法来评估这些 LOAD小鼠模型，其中包括行为/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学 分析、蛋白质组学、微生物组和代谢组学研究，包括筛选新型生物流体 与进展至LOAD相关的标志物。UCI MODEL-AD将利用我们的NIA资助的资源， 阿尔茨海默病研究中心与加速药物伙伴关系计划相结合， 阿尔茨海默病（AMP-AD）和其他人类AD数据集，以促进从这些数据集获得的数据的对齐。 小鼠模型以人类为条件，确定最佳小鼠模型，供国际AD研究使用 社区所有数据和模型都将通过杰克逊实验室（JAX）不受限制地提供，并且 数据可通过modeladexplorer.org网站浏览，原始数据可通过 AD知识门户。