Systems Genetic Analysis of Cognitive Resilience Using Multi-Parent Crosses

我们建议对正常人类认知老化的决定因素进行首次全面分析 使用系统遗传学资源--多样性远系繁殖小鼠小组，DO--专门设计用于建模 人类群体的遗传和表型变异。这个项目的目标是确定遗传因素 以及导致正常认知老化和病理性脑老化的潜在机制。大- 大规模的人类遗传学研究对于理解个体的遗传构成之间的联系至关重要， 以及他们发展认知能力下降和阿尔茨海默病（AD）的风险。然而，发现具体 由于缺乏对认知功能的纵向测量， 认知和神经生理变化，许多环境混乱，以及难以获得 在疾病的早期无症状阶段的分子数据。虽然小鼠模型提供了重要的实验 对照纵向和横截面老化研究，传统的近交系不概括 基因多样性，以确定人类疾病相关的候选基因。该提案试图 通过测试使用我们的DO发现的候选基因的翻译相关性来克服这些限制 对照来自人类队列的数据。由于年龄和遗传是AD的主要危险因素，我们 假设遗传因素是正常认知老化变异的基础（从极端风险到 弹性）参与AD认知症状的发展。我们将采取系统遗传 方法来确定基因和潜在的分子和细胞机制，改变发病年龄， 一组雄性和雌性DO小鼠中认知老化的严重程度（目的1）。候选基因和网络将 测试与人类正常衰老和AD队列的相关性，以确定保守的弹性因素 人类（目标2）。我们将测试这些预测促进健康大脑衰老的候选基因的作用 （弹性），以及与从正常认知老化向AD的负向转变相关的那些 病理生理学（目标3）。具体的创新（除了DO鼠标）包括使用多尺度网络 鉴定能够区分扰动和网络的弹性蛋白的方法， 从那些仅仅相关的认知弹性;我们的跨物种翻译平台测试 在多个人类队列的小鼠中确定的候选者; 杰克逊实验室，该实验室将用于基因验证和精确AD模型的创建;以及我们的 人类和小鼠遗传学、生物信息学、高分辨率显微镜和功能 验证。影响：我们将发现和验证促进健康大脑衰老和抗AD能力的目标 并将为认知恢复力提供机制性的见解。遗传因素的识别和 在正常认知老化的基础变化机制，并导致病理性脑老化，将可能 指出新的治疗策略，包括可能在AD症状发作前使用的策略。

We propose to conduct the first comprehensive analysis of the determinants of normal human cognitive aging using a systems genetics resource—the Diversity Outbred panel of mice, DO—specifically designed to model the genetic and phenotypic variation of human populations. The goal of this project is to identify genetic factors and mechanisms underlying variation in normal cognitive aging, and that lead to pathologic brain aging. Large- scale human genetics studies have been central to understanding links between an individual’s genetic make- up and their risk for developing cognitive decline and Alzheimer’s Disease (AD). However, discovery of specific factors in humans has been impeded by the lack of longitudinal measures of cognitive function, heterogeneity of cognitive and neurophysiological changes, numerous environmental confounds, and difficulty obtaining molecular data at the early asymptomatic stages of disease. While mouse models offer significant experimental control for longitudinal and cross-sectional aging studies, conventional inbred strains do not recapitulate the genetic diversity necessary to identify human disease–relevant candidate genes. This proposal attempts to surmount these limitations by testing the translational relevance of gene candidates discovered using our DO panel against data from human cohorts. Since age and genetics are the leading risk factors for AD, we hypothesize that genetic factors underlying variation in normal cognitive aging (ranging from extreme risk to resilience) are involved in the development of cognitive symptoms in AD. We will take a systems genetic approach to identify genes and potential molecular and cellular mechanisms that modify the age at onset and severity of cognitive aging in a cohort of male and female DO mice (Aim 1). Candidate genes and networks will be tested for associations against normal aging and AD cohorts in humans to identify resilience factors conserved in humans (Aim 2). We will test the role of these candidate genes predicted to promote healthy brain aging (resilience), as well as those associated with a negative shift from normal cognitive aging toward AD pathophysiology (Aim 3). Specific innovations (in addition to the DO mice) include the use of multi-scale network methods to identify resilience proteins that are capable of distinguishing perturbations and networks that initiate cognitive resilience from those that merely correlate; our cross-species translational platform for testing candidates identified in mice in multiple human cohorts; the unmatched mouse resources and expertise of The Jackson Laboratory, which will be leveraged for gene validation and creation of precision AD models; and our team of experts in human and mouse genetics, bioinformatics, high-resolution microscopy and functional validation. IMPACT: We will discover and validate targets for promoting healthy brain aging and resilience to AD and will provide mechanistic insight into cognitive resilience. The identification of genetic factors and mechanisms underlying variation in normal cognitive aging, and that lead to pathologic brain aging, will likely point to novel therapeutic strategies, including ones that may be used before the onset of AD symptoms.