Molecular Clock Control of Oxidative Metabolism in Metabolic Disease

代谢疾病中氧化代谢的分子钟控制

• 批准号: 8278459
• 负责人: Clara Bien Peek
• 金额: $ 5.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278459
• 关键词: ATP Synthesis Pathway; Ablation; Acetylation; Affect; Anabolism; Animals; Biochemical; Catabolism; Cell Respiration; Cell physiology; Cells; Cessation of life; Circadian Rhythms; Coupling; Deacetylation; Defect; Development; Diabetes Mellitus; Enzymes; Exhibits; Experimental Genetics; Family; Fasting; Functional disorder; Gene Expression; Generations; Genes; Genetic; Gluconeogenesis; Goals; Hepatic Tissue; Hepatocyte; Histones; Homeostasis; Hour; Human; Hypoglycemia; Ketones; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lipids; Liver; Lysine; Mammalian Cell; Measures; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Muscle; Mutant Strains Mice; Mutation; Myopathy; Nicotinamide adenine dinucleotide; Nonesterified Fatty Acids; Nutrient; Obesity; Oxygen; Pathway interactions; Phenotype; Physiological; Play; Post-Translational Protein Processing; Prevalence; Production; Protein Acetylation; Proteins; Proteome; Proteomics; Pyruvate; Regulation; Regulatory Pathway; Research; Research Personnel; Research Proposals; Respiration; Role; Signal Transduction; Sirtuins; Skeletal Muscle; Sleep; System; Testing; Time; Transcriptional Regulation; Variant; circadian pacemaker; diet and exercise; fatty acid oxidation; feeding; impaired glucose tolerance; insulin secretion; ketogenesis; member; mitochondrial dysfunction; mutant; research study; skeletal; stem; transcription factor; urea cycle

DESCRIPTION (provided by applicant): Research over the past decade has uncovered a connection between circadian clocks and metabolic homeostasis. Mice lacking components of the molecular clock develop dramatic metabolic abnormalities, including obesity, disrupted glucoregulation, elevated free fatty acids and metabolic myopathy. Although the molecular mechanisms underlying these phenotypes remain poorly understood, many of these defects point to disruptions in mitochondrial oxidative metabolic pathways, including fatty acid oxidation and respiration. A major clue concerning the cause of mitochondrial dysfunction in circadian mutants stems from the recent discovery that the clock transcription factor loop regulates cellular levels of NAD+, and in turn, controls activity of the sirtuin family of NAD+-dependent deacetylases, key factors in oxidative metabolism. In exciting new results, we also now show that circadian mutant mice exhibit hyperacetylation of several mitochondrial enzymes that are rate-limiting in the urea cycle, ketone production, fatty acid oxidation and ATP synthesis. My research proposal will thus build upon my previous studies of oxygen-dependent control of metabolic transcription factor pathways and specifically test the hypothesis that circadian gene disruption leads to impaired oxidative metabolism due to dysregulation of NAD+ synthesis and activity of mitochondrial-localized sirtuin enzymes. The proposed experiments will exploit experimental genetic, biochemical and cell physiological approaches and will serve as an invaluable vehicle in my development as an independent investigator in metabolism research.

描述（由申请人提供）：过去十年的研究发现了生物钟与代谢稳态之间的联系。缺乏分子钟成分的小鼠会出现严重的代谢异常，包括肥胖、葡萄糖调节紊乱、游离脂肪酸升高和代谢性肌病。尽管这些表型背后的分子机制仍然知之甚少，但其中许多缺陷表明线粒体氧化代谢途径（包括脂肪酸氧化和呼吸）受到破坏。关于昼夜节律突变体线粒体功能障碍原因的一个主要线索源于最近的发现，即时钟转录因子环调节细胞中 NAD+ 的水平，进而控制 NAD+ 依赖性脱乙酰酶的 Sirtuin 家族的活性，而 NAD+ 依赖性脱乙酰酶是氧化代谢的关键因素。在令人兴奋的新结果中，我们现在还表明，昼夜节律突变小鼠表现出几种线粒体酶的过度乙酰化，这些酶在尿素循环、酮产生、脂肪酸氧化和 ATP 合成中具有限速作用。因此，我的研究计划将建立在我之前对代谢转录因子途径的氧依赖性控制的研究基础上，并专门测试这样的假设：由于 NAD+ 合成和线粒体定位的 Sirtuin 酶活性失调，昼夜节律基因破坏导致氧化代谢受损。拟议的实验将利用实验遗传、生化和细胞生理学方法，并将作为我作为代谢研究独立研究者的发展的宝贵工具。