Genetic control of quantitative traits associated with the metabolic syndrome

与代谢综合征相关的数量性状的遗传控制

• 批准号: 8061951
• 负责人: MARIA DE LUCA
• 金额: $ 31.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061951
• 关键词: Adipose tissue; Affect; Aging; Alabama; Animals; Biochemical; Biochemical Genetics; Bioenergetics; Body fat; Candidate Disease Gene; Chromosome Mapping; Clinical; Coronary heart disease; Coupling; Data; Defect; Drosophila genus; Drosophila melanogaster; Dyslipidemias; Eating; Energy Metabolism; Eukaryota; Fatty acid glycerol esters; Female; Fertility; Food Supply; Generations; Genes; Genetic; Genetic Variation; Genomics; Genotype; Glucose; Growth; Health; High Density Lipoproteins; Homeostasis; Human; Hypertension; Immune response; Immunocompetence; Inbreeding; Individual; Infection; Inflammatory; Knowledge; Link; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Molecular Target; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Orthologous Gene; Outcome; Outcomes Research; Oxidative Stress; Pathway Analysis; Pathway interactions; Phenotype; Plasma; Population; Prevention; Production; Property; Proteins; Protons; Public Health; Reactive Oxygen Species; Regulation; Regulator Genes; Reporting; Reproduction; Resources; Respiration; Risk Factors; Rodent; Sampling; Skeletal Muscle; Testing; Therapeutic; Transcript; Variant; Whole Organism; Work; base; coping; design; fighting; fly; functional genomics; genetic element; genetic variant; genome sequencing; genome wide association study; improved; insight; insulin sensitivity; life history; molecular marker; mutant; population based; public health relevance; research study; theories; trait; treatment strategy

DESCRIPTION (provided by applicant): Recent biochemical and genetic evidence provides strong support that obesity and related metabolic disorders develop from defects in mitochondrial function. These defects produce excess cellular oxidative stress mediated by reactive oxygen species (ROS). One mechanism that appears to improve outcomes in metabolic disorders is mitochondrial proton leak, i.e., the uncoupling of energy production from respiration in the mitochondria. Mild uncoupling in mitochondrial respiration mediated by uncoupling proteins (UCPs) has been reported to decrease fat storage and ROS production in animals and favorably modifies insulin sensitivity. Using 18 unrelated wild-type inbred lines of D. melanogaster, we have shown that naturally occurring genetic variation affects inter-individual variability in mitochondrial state 4 respiration rates (e.g. basal proton leak) in skeletal muscles. We have also shown that variation in mitochondrial state 4 respiration rates in skeletal muscles is negatively correlated with variation in fat storage. This implies that some genotypes have higher mitochondrial coupling efficiency and store higher quantities of fat while other genotypes have lower coupling efficiency and require more energy for maintaining their mitochondrial electrochemical gradient. These observations raise the important question of why variation in mitochondrial proton leak (e.g. metabolic inefficiency) is evolutionary conserved in natural populations. We speculate that the trade-off between mitochondrial state 4 respiration and fat storage observed in our preliminary studies is a reflection of the allocation of finite resources between competing organismal functions. Our hypothesis is that while individuals with efficient mitochondrial coupling can successfully use their fat storage for reproduction and for coping with environmental challenges, such as fighting infection, those with less coupling efficiency will need to use more energy for maintaining their mitochondrial electrochemical gradient at the expense of other organismal functions. However, mitochondrial basal proton leak may decrease ROS generation and, therefore, protect against cellular degeneration and aging. The Specific Aims of this project are to: (1) Perform a genome-wide association scan to map genetic variants affecting naturally occurring variation in muscle-specific mitochondrial bioenergetics, ROS production, energy metabolism traits, food intake, innate immune response, and female fecundity. (2) Determine the gene co-expression network regulating mitochondrial bioenergetic traits in young flies (3-5 days old). (3) Verify whether 10 of the "hub genes" identified by the analyses performed in Aim 2 are responsible for the coordinated regulation of mitochondrial bioenergetics and also impact whole-organism energy homeostasis and life-history traits. (4) Investigate whether genetic variants in human orthologs of the 10 Drosophila candidate genes identified in the previous aims are associated with phenotypic variation in human obesity and related metabolic outcomes. These studies will provide new insights into the genetic basis of mitochondrial coupling efficiency as it relates to metabolic, immune response and life-history traits. PUBLIC HEALTH RELEVANCE: The proposed study has been designed to identify the regulatory genes that control inter-individual variability in skeletal muscle-specific mitochondrial coupling efficiency, whole-body energy metabolism, immunocompetence, and organismal life-history traits. These genetic pathways will be identified by integrating genetic and expression network analysis in Drosophila melanogaster. Using this information, human population-based association studies will be performed to investigate the effect of natural variation in the identified regulatory genes on quantitative traits associated with the metabolic syndrome.

描述（由申请人提供）：最近的生化和遗传证据提供了强有力的支持，即肥胖和相关代谢性疾病从线粒体功能的缺陷中发展出来。这些缺陷会产生由活性氧（ROS）介导的过量细胞氧化应激。一种似乎改善代谢性疾病结果的机制是线粒体质子泄漏，即，在线粒体中呼吸中能量产生的偶联。据报道，通过解偶联蛋白（UCP）介导的线粒体呼吸中的轻度解偶将可减少动物的脂肪储存和ROS产生，并有利地改变了胰岛素敏感性。使用D. melanogaster的18种无关的野生型近交系，我们表明，天然存在的遗传变异会影响骨骼肌中线粒体4呼吸率（例如基底质子泄漏）的个体间变异性。我们还表明，线粒体状态4骨骼肌4呼吸率的变化与脂肪储存的变化负相关。这意味着某些基因型具有较高的线粒体耦合效率，并且储存较高的脂肪，而其他基因型的耦合效率较低，并且需要更多能量来维持其线粒体电化学梯度。这些观察结果提出了一个重要的问题，即为什么线粒体质子泄漏（例如代谢效率低下）的变化在天然种群中是进化保守的。我们推测，在我们的初步研究中观察到的线粒体状态4呼吸与脂肪储存之间的权衡是反映了竞争有机体功能之间有限资源的分配。我们的假设是，尽管有效的线粒体耦合的个体可以成功地利用其脂肪存储来繁殖并应对环境挑战，例如抗击感染，但耦合效率较低的人需要使用更多能量来维持其线粒体电化学梯度，并以其他生物体功能为费用。但是，线粒体基底质子泄漏可能会减少ROS的产生，因此可以预防细胞变性和衰老。该项目的具体目的是：（1）执行全基因组关联扫描以绘制影响遗传变异的，影响肌肉特异性的线粒体生物能学，ROS产生，能量代谢性状，食物摄入量，先天性绝对免疫反应和女性繁殖力。 （2）确定调节年轻蝇（3-5天大）线粒体生物能性状的基因共表达网络。 （3）验证AIM 2中进行的分析确定的10个“集线器基因”是否负责线粒体生物能学的协调调节，还影响了全体生物的能量能量稳态和生活历史性状。 （4）研究以前目标中鉴定出的10种果蝇候选基因的人类直系同源物中的遗传变异是否与人肥胖和相关代谢结果的表型变异有关。这些研究将为与代谢，免疫反应和生活历史性状有关的线粒体耦合效率的遗传基础提供新的见解。 公共卫生相关性：拟议的研究旨在确定控制骨骼肌肉特异性线粒体耦合效率，全身能量代谢，免疫能力和生物体生命创che的调节基因。这些遗传途径将通过整合果蝇中的遗传和表达网络分析来识别。使用这些信息，将进行基于人群的关联研究，以研究确定的调节基因自然变异对与代谢综合征相关的定量性状的影响。