Translational Systems Genetics of Mitochondria, Metabolism, and Aging

描述(申请人提供)：新陈代谢紊乱，通常与线粒体功能有关，对人类人群的疾病风险和健康寿命有重大影响。2型糖尿病、非酒精性脂肪性肝病、高血压、高脂血症和心血管疾病都与代谢和线粒体功能的重大变化有关。一系列复杂的遗传和环境因素--包括饮食--是代谢综合征风险和严重程度的个体差异的基础。这个项目的重点是复杂的基因-环境相互作用(GxE)，它有助于线粒体和代谢综合征，并减少健康寿命。我们使用一种新的综合系统遗传学方法来研究高脂肪西方饮食的影响。这项工作依赖于一大类等基因和遗传多样性的小鼠品系--包括F1杂交种--它们在简化论和综合主义方法之间起到了转换和机械桥梁的作用。相同的队列将被作为年龄的函数进行研究，饮食明显不同。在目标1中，我们使用BXD品系和非近交系但等基因的雌性F1队列在高脂和低脂饮食下研究了它们的寿命。我们定位并量化了新的GxE型修饰基因座、候选基因和调节健康和长寿的分子网络。在目标2中，我们生成随年龄和饮食变化的深层分子、线粒体和代谢生物标记物数据。我们预计，基因变异和饮食将与线粒体功能和关键器官和组织的新陈代谢有因果关系。在目标3中，我们对复杂的和集成的分子和细胞网络进行建模，这些网络定义了生命力和健康寿命的差异。我们使用复杂的生物信息学和统计框架(eQTL分析、方差分析和结构方程建模)。最后，在目标4中，我们验证并翻译了涉及新陈代谢、线粒体和健康范围的网络。我们在线虫中使用获得和失去功能的策略来测试候选基因。我们通过测试161,000名绝经后妇女(妇女健康倡议数据集)的相关性来评估候选基因和生物标记物的翻译相关性。WHI是测试饮食效果的理想翻译伴侣。该项目将(1)确定与代谢性疾病和健康寿命有关的高影响变异和分子/代谢网络，(2)提供一个实验和预测系统生物学框架，将人类群体中的基因和环境因素与疾病风险联系起来。

DESCRIPTION (provided by applicant): Disturbances of metabolism, often linked to mitochondrial function, have a major impact on disease risk and healthspan among human populations. Type 2 diabetes mellitus, non-alcoholic fatty liver disease, hypertension, hyperlipidemia, and cardiovascular diseases are all linked to major changes in metabolic and mitochondrial function. A complex set of genetic and environmental factors-including diet-underlie individual differences in the risk and severity of metabolic syndrome. This project is focused on the complex gene-by- environmental interactions (GXE) that contribute to mitochondrial and metabolic syndrome, and that reduce healthy lifespan. We use a new integrative systems genetics approach to study effects of a high fat Western diet. This work relies on a large family of isogenic and genetically diverse murine lines-including F1 hybrids- that serve as a translational and mechanistic bridge between reductionist and integrative approaches. Identical cohorts will be studied as a function of age on markedly different diets. In Aim 1, we study lifespan using BXD strains and non-inbred but isogenic F1 cohorts of females under high and low fat diets. We map and quantify novel GXE-type modifier loci, candidate genes, and molecular networks that modulate healthspan and longevity. In Aim 2 we generate deep molecular, mitochondrial, and metabolic biomarker data as a function of age and diet. We expect that gene variants and diet will be causally linked to mitochondrial function and to metabolism in key organs and tissues. In Aim 3 we model complex and integrative molecular and cellular networks that define differences in vitality and healthspan. We use sophisticated bioinformatic and statistical frameworks (eQTL analysis, ANOVA, and structural equation modeling). Finally, in Aim 4 we validate and translate networks involved in metabolism, mitochondria, and healthspan. We test candidate genes using gain- and loss-of-function strategies in C. elegans. We evaluate translational relevance of candidate genes and biomarkers by testing for associations in a remarkably well studied cohort of 161,000 postmenopausal women (Women's Health Initiative data sets). The WHI is an ideal translation companion to test effects of diet. This project will (1) identify high impact variants and molecular/metabolic networks involved in metabolic diseases and healthspan, and (2) provide an experimental and predictive systems biology framework that links genotype and environmental factors to disease risk in human populations.