Systems Genetic Analysis of Cognitive Resilience Using Multi-Parent Crosses

使用多亲本杂交进行认知弹性的系统遗传分析

• 批准号: 10840565
• 负责人: CATHERINE COOK KACZOROWSKI
• 金额: $ 155.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10840565
• 关键词: Systems; Genetic; Analysis; Cognitive; Resilience

PROJECT SUMMARY/ABSTRACT 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. Largescale human genetics studies have been central to understanding links between an individual’s genetic makeup 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 mouse resources and expertise of The Kaczorowski 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 A 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.

项目摘要/摘要 我们建议对正常人类认知衰老的确定进行首次综合分析 使用系统遗传学资源（多样性杂种小鼠），专门设计用于建模 人群的遗传和表型变异。该项目的目的是确定遗传因素 正常认知衰老的差异和导致病理脑衰老的机制。 LargesCale人类遗传学研究对于理解个人遗传之间的联系至关重要 化妆及其发展认知能力下降和阿尔茨海默氏病（AD）的风险。但是，发现 缺乏认知功能的纵向测量，阻碍了人类的特定因素， 认知和神经生理学变化的异质性，许多环境混淆和困难 在疾病的早期渐进阶段获得分子数据。鼠标模型可显着 纵向和横断面衰老研究的实验对照，常规的近交菌株不会 概括鉴定人类疾病 - 杂种候选基因所需的遗传多样性。这个建议 试图通过测试发现的基因候选者的翻译相关性来克服这些限制 使用我们的DO面板来抵制人类人群的数据。由于年龄和遗传学是领先的风险因素 AD，我们假设正常认知衰老的遗传因素是基本的遗传因素（范围从极端 弹性的风险）参与了AD中认知症状的发展。我们将采用系统通用 鉴定基因以及潜在的分子和细胞机制，以改变发作时的年龄和细胞机制 男性和雌性DO小鼠队列中认知衰老的严重程度（AIM 1）。候选基因和网络将 在人类中对正常衰老和AD队列的关联进行测试以识别弹性因素 在人类中保守（目标2）。我们将测试这些候选基因的作用，预计将促进健康 大脑衰老（韧性），以及与正常认知衰老的负面转变相关的脑衰老 AD病理生理学（AIM 3）。特定的创新（除了DO小鼠之外）还包括使用多尺度 网络方法识别能够区分扰动和网络的弹性蛋白 那些仅相关的人会启动认知的韧性；我们的跨物种翻译平台 测试在多个人类人群中在小鼠中鉴定出的候选者；鼠标资源和专业知识 Kaczorowski实验室，该实验室将用于基因验证和精确广告模型的创建；和 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的专家团队 验证。影响：我们将发现并验证目标，以促进健康的大脑衰老和韧性 并将提供有关认知弹性的机械洞察力。遗传因素和 正常认知衰老和导致病理大脑衰老的机制可能会发生变化 指出了新颖的治疗策略，包括在AD符号开始之前可以使用的策略。