Translational Systems Genetics of Mitochondria, Metabolism, and Aging

描述（由申请人提供）：代谢紊乱通常与线粒体功能有关，对人群的疾病风险和健康寿命有重大影响。2型糖尿病、非酒精性脂肪肝、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。一组复杂的遗传和环境因素包括饮食构成了代谢综合征风险和严重程度的个体差异。该项目的重点是复杂的基因与环境的相互作用（GXE），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。这项工作依赖于一个大家庭的同基因和遗传多样性的小鼠品系，包括F1杂交-作为一个翻译和机械之间的桥梁还原和综合的方法。相同的队列将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品系和非近交但同基因的F1雌性队列在高脂肪和低脂肪饮食下研究寿命。我们绘制并量化了新的GXE型修饰基因座、候选基因和调节健康寿命和寿命的分子网络。在目标2中，我们生成了作为年龄和饮食函数的深层分子、线粒体和代谢生物标志物数据。我们预计基因变异和饮食将与线粒体功能以及关键器官和组织的代谢有因果关系。在目标3中，我们对定义活力和健康寿命差异的复杂和整合的分子和细胞网络进行建模。我们使用复杂的生物信息学和统计框架（eQTL分析，ANOVA和结构方程模型）。最后，在目标4中，我们验证和翻译涉及代谢，线粒体和健康的网络。我们在C中使用功能获得和功能丧失策略测试候选基因。优雅我们通过对161，000名绝经后妇女（妇女健康倡议数据集）进行充分研究的队列中的相关性测试，评估候选基因和生物标志物的翻译相关性。WHI是测试饮食效果的理想翻译伴侣。该项目将（1）确定参与代谢疾病和健康跨度的高影响变体和分子/代谢网络，（2）提供一个实验和预测系统生物学框架，将基因型和环境因素与人群中的疾病风险联系起来。

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.