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。一系列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-环境相互作用（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的等基因和遗传多样性的小鼠系家族——包括F1杂交种——作为还原论和综合方法之间的翻译和机制桥梁。将研究相同的队列在明显不同的饮食上的年龄函数。在Aim 1中，我们使用BXD菌株和非近交系但等基因的F1雌性在高脂肪和低脂肪饮食下研究寿命。我们绘制和量化了新的gxe型修饰位点、候选基因和调节健康寿命和寿命的分子网络。在Aim 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和关键器官和组织的代谢有因果关系。在Aim 3中，我们模拟了复杂和综合的分子和细胞网络，定义了活力和健康跨度的差异。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模型）。最后，在Aim 4中，我们验证并翻译了代谢、线粒体和健康跨度相关的网络。我们在秀丽隐杆线虫中使用功能获得和功能丧失策略测试候选基因。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进行相关性测试，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伙伴。该项目将(1)确定与代谢性疾病和健康相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.