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。 使用一种系统遗传学资源--DO的多样性异种小鼠小组--专门设计用来模拟 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的潜在机制，以及导致病理性脑老化的机制。大号- 大规模的人类遗传学研究对于理解个体的基因构成之间的联系至关重要。 增加他们患认知功能减退和阿尔茨海默病(AD)的风险。然而，发现特定的 人类的因素由于缺乏对认知功能的纵向测量而受到阻碍， 认知和神经生理的变化，大量的环境混乱，以及难以获得 疾病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性 在纵向和横断面老化研究中，常规近交系不能概括 识别人类疾病相关候选基因所需的遗传多样性。这项提议试图 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 专家小组反对来自人类队列的数据。由于年龄和遗传因素是AD的主要风险因素，我们 假设正常认知老化的遗传因素(从极端风险到 复原力)参与AD认知症状的发展。我们将采取一种系统基因 一种识别基因和潜在的分子和细胞机制的方法，这些基因和潜在的分子和细胞机制改变了发病年龄和 雄性和雌性DO小鼠队列中认知老化的严重程度(目标1)。候选基因和网络将 在人类中测试与正常衰老和AD队列的相关性，以确定保存的弹性因素 在人类身上(目标2)。我们将测试这些预测会促进大脑健康老化的候选基因的作用 (恢复力)，以及与从正常认知老化向AD的负面转变相关的那些 病理生理学(目标3)。具体的创新(除了DO MICE之外)包括使用多尺度网络 识别能够区分扰动和启动网络的弹性蛋白的方法 认知韧性来自那些仅仅相关的人；我们用于测试的跨物种翻译平台 在多个人类队列中的小鼠中确定的候选对象；无与伦比的小鼠资源和 杰克逊实验室，该实验室将用于基因验证和创建精确的AD模型；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：我们将发现并验证促进大脑健康老化和应对AD的目标 并将提供对认知韧性的机械性洞察。遗传因素和遗传因素的识别 正常认知衰老的潜在机制，以及导致病理性脑老化的机制，很可能 指出新的治疗策略，包括可能在阿尔茨海默病症状出现之前使用的策略。

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.