Translational Systems Genetics of Mitochondria, Metabolism, and Aging

线粒体、代谢和衰老的转化系统遗传学

基本信息

批准号：
8852521
负责人：
ROBERT W. WILLIAMS
金额：
$ 49.06万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8852521
关键词：
Age Aging Analysis of Variance Biochemical Pathway Bioinformatics Biological Markers Blood Caenorhabditis elegans Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cell Aging Cohort Studies Collaborations Companions Complex Data Data Set Databases Diet Disease Environmental Risk Factor Equation Exons Family Fat-Restricted Diet Fatty acid glycerol esters Female Gene Expression Profile Genes Genetic Genetic Variation Genetic screening method Genetically Engineered Mouse Genotype Goals Health Homeostasis Human Hybrids Hyperlipidemia Hypertension Inbreeding Individual Differences Learning Link Liver Liver diseases Longevity Maps Measures Metabolic Metabolic Diseases Metabolic syndrome Metabolism Metadata Methods Mitochondria Mitochondrial Diseases Modeling Molecular Morphology Mus Muscle Myocardium National Heart, Lung, and Blood Institute Network-based Non-Insulin-Dependent Diabetes Mellitus Organ Pathogenesis Pathway Analysis Phenotype Pilot Projects Population Population Heterogeneity Postmenopause Quantitative Trait Loci Recombinants Research Design Resources Risk Serum Severities System Systems Biology Testing Tissues Translating Translations Validation Variant Weight Woman Women&apos s Health Work animal tissue biobank clinical phenotype clinically relevant cohort computer based statistical methods density design disorder risk feeding gene interaction genetic approach genetic resource genetic variant genome sequencing genome wide association study loss of function mitochondrial dysfunction molecular phenotype mouse model multi-scale modeling multidisciplinary non-alcoholic fatty liver novel protein expression reverse genetics trait transcriptome sequencing western diet

项目摘要

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.

描述（由申请人提供）：代谢的障碍通常与线粒体功能有关，对人类种群中的疾病风险和健康状态有重大影响。 2型糖尿病，非酒精性脂肪肝病，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。一组复杂的遗传和环境因素，包括代谢综合征的风险和严重程度的饮食饮食中的个体差异。该项目的重点是有助于线粒体和代谢综合征的复杂基因相互作用（GXE），并降低了健康的寿命。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众多的等生和遗传多样的鼠系，包括F1杂种，它们是还原主义和综合方法之间的转化和机械桥梁。同一人群将根据年龄明显不同的饮食进行研究。在AIM 1中，我们使用BXD菌株和高脂饮食下的女性的非雌性F1同龄人来研究寿命。我们绘制并量化了调节健康范围和寿命的新型GXE型修饰剂基因座，候选基因和分子网络。在AIM 2中，我们产生了深层分子，线粒体和代谢生物标志物数据，这是年龄和饮食的函数。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中的代谢有因果关系。在AIM 3中，我们对定义活力和健康范围差异的复杂和整合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和结构方程建模）。最后，在AIM 4中，我们验证和翻译有关代谢，线粒体和HealthSpan的网络。我们使用秀丽隐杆线虫中的功能丧失策略测试候选基因。我们通过在经过深入研究的161,000名绝经后妇女（妇女健康计划数据集）中测试相关的协会来评估候选基因和生物标志物的转化相关性。 WHI是饮食测试作用的理想翻译伴侣。该项目将（1）确定参与代谢疾病和HealthSpan涉及的高影响变异和分子/代谢网络，以及（2）提供了一个实验性和预测性系统生物学框架，将基因型和环境因素与人群中的疾病风险联系起来。