Disease Model Development and Phenotyping Project

摘要 疾病模型开发和表型项目(DMP)的目标是开发新的小鼠模型 迟发性阿尔茨海默病(LOAD)的研究，以深入表型这些模型，并使所有数据和小鼠 可用的菌株使研究人员能够选择最佳的小鼠模型和时间点用于治疗和 干预测试，以及关于负载机制的假设的测试。在过去 五年来，我们已经用我们的基础遗传平台的一个组件培育出了表型深刻的小鼠 App基因的Aü区域被人源化了，我们最近引入了第二个成分， 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 替换以建模和验证9个GWAS确定的负荷风险变量，并对每个变量的小鼠进行分析 野生型和5xFAD背景下的变异体，以确定它们对斑块生成和损伤的影响 对大脑施加的对病理的反应。在这个续篇中，我们将使用这些分析的结果，加上 来自FGBDMC和文献的输入，以确定最有可能的负荷风险变量组合 在设计的两条互补的hab-ki、hTAU、hAPOE4平台线上加载并引入它们 以模仿最近定义的AD的子类型。这些型号将在其 评估变异对病理发展和随后的组织损伤的影响的寿命 与衰老相结合。UCI模型-AD小组使用一种综合方法来评估这些 负荷小鼠模型，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，整体和单细胞rna-seq，单细胞水平空间转录 分析、蛋白质组学、微生物组和代谢组研究，包括筛选新的生物体液 与加载进度相关联的标记。UCI模式-AD将利用我们由NIA资助的资源 阿尔茨海默病研究中心与加速药物伙伴计划 阿尔茨海默病(AMP-AD)和其他人类AD数据集，以促进从这些数据获得的数据对齐 根据人体状况确定最佳的老鼠模型供国际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，以及 数据可通过modadexplorer.org网站浏览，原始数据可通过免费下载 广告知识门户。

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.