Epigenomic regulation of metabolism in muscle by circadian clock and environment

生物钟和环境对肌肉代谢的表观基因组调节

• 批准号: 8568216
• 负责人: Zheng Sun
• 金额: $ 9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568216
• 关键词: Address; Affect; Amino Acids; Animal Model; Animals; Back; Binding; Biochemistry; Bioinformatics; Branched-Chain Amino Acids; Burn injury; Carbohydrates; Catabolism; Chromatin; Circadian Rhythms; Citric Acid Cycle; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Core Facility; Coupled; Darkness; Data; Data Set; Development; Diabetes Mellitus; Diet; Dietary Factors; Disease; Economic Burden; Energy Metabolism; Environment; Euglycemic Clamping; Exercise; Fatty acid glycerol esters; Funding Opportunities; Future; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Glucose; Glucose Clamp; Glucose Intolerance; Glycogen; Glycolysis; Goals; Health; Hepatic; Histone Deacetylase Inhibitor; Histones; Homeostasis; Inflammatory; Insulin Resistance; Isotopes; Ketone Bodies; Ketones; Knockout Mice; Knowledge; Laboratories; Lead; Light; Lipids; Liver; Malignant Neoplasms; Mediating; Mentors; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Modification; Molecular; Monitor; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Output; Oxygen Consumption; Pennsylvania; Performance; Phase; Physiology; Play; Purine Nucleotides; Recruitment Activity; Regulation; Research; Role; Running; Signal Transduction; Skeletal Muscle; Societies; Source; Testing; Thermogenesis; Time; Tissues; Universities; carbohydrate metabolism; career; circadian pacemaker; data mining; epigenome; epigenomics; feeding; flexibility; gene environment interaction; genome-wide; glucose tolerance; glucose uptake; histone deacetylase 3; improved; insulin sensitivity; lipid metabolism; metabolomics; mitochondrial dysfunction; mouse model; novel; pandemic disease; preference; public health relevance; research study; respiratory; response; small molecule

DESCRIPTION (provided by candidate): The current research is to study how epigenomic modifier histone deacetylase 3 (HDAC3) regulates carbohydrates metabolism and insulin sensitivity in skeletal muscle in response to either the internal circadian clock or the external dietary factor. I have developed a novel mouse model with HDAC3 specifically depleted in skeletal muscle, and have found that the mice display disrupted metabolic circadian gene expression and exacerbated glucose intolerance that is induced by high fat diet (HFD). During the mentored phase, I will gain new expertise in genome-wide epigenomic approaches that are well established in my mentor's laboratory. I will also gain additional knowledge in muscle physiology, metabolic flux analysis, and metabolomics methods through collaboration with other laboratories and core facilities at University of Pennsylvania. The research that I propose to continue in the independent phase is to study HDAC3 in exercise endurance, fuel selection and efficiency, as well as lipid and amino acid metabolism in skeletal muscle. We have found that mice without muscular HDAC3 have surprisingly improved exercise endurance associated with a switch in fuel preference from carbohydrates towards lipid. I will characterize mitochondrial function and trace metabolic fluxes through lipid, ketone bodies, and amino acids catabolism, including the anaplerotic purine nucleotide cycle, in exercising animals as well as in isolated primary myocytes, where knockdown experiments will test the requirement of specific HDAC3 target genes for the observed fuel selection and enhanced fuel efficiency. My future career goal after independence is to decipher the epigenomic mechanism that underlies hormetic response to physical exercise in skeletal muscle. Exercise is beneficial to many aspects of health, especially in the context of obesity and diabetes. My general hypothesis is that epigenomic mechanisms underlie exercise- induced beneficial metabolic remodeling. I will comprehensively characterize exercise-induced changes in skeletal muscle transcriptome and epigenome using genome-wide methods and metabolomics approaches. This is the first endeavor ever, as far as I know, to analyze exercise-induced epigenomic changes in a genome-wide scale. This unbiased method will produce comprehensive datasets, from which data mining and motif analysis will generate new hypotheses regarding novel transcription networks that respond to exercise. Biochemistry methods and metabolic flux analysis will then be used to validate these hypotheses, followed by development of genetic animal models and physiology studies. Together, these approaches will generate testable hypothesis backed up by preliminary data, which is essential for successful competition for future funding opportunities.

描述（由候选人提供）：目前的研究是研究表观基因组修饰剂组蛋白脱乙酰酶3（HDAC 3）如何调节骨骼肌中的碳水化合物代谢和胰岛素敏感性，以响应内部昼夜节律钟或外部饮食因素。我已经开发了一种新的小鼠模型，其中HDAC3在骨骼肌中特异性耗尽，并且发现小鼠显示出破坏的代谢昼夜节律基因表达和由高脂饮食（HFD）诱导的葡萄糖耐受不良加剧。在指导阶段，我将获得新的专业知识，在全基因组表观基因组的方法，是很好地建立在我的导师的实验室。我还将通过与宾夕法尼亚大学其他实验室和核心设施的合作，获得肌肉生理学，代谢通量分析和代谢组学方法方面的额外知识。我建议在独立阶段继续进行的研究是研究HDAC3在运动耐力，燃料选择和效率以及骨骼肌中的脂质和氨基酸代谢方面的作用。我们已经发现，没有肌肉HDAC3的小鼠具有令人惊讶地改善的运动耐力，这与燃料偏好从碳水化合物向脂质的转变有关。我将通过脂质，酮体，和氨基酸catenoids，包括回补嘌呤核苷酸循环，在运动动物以及分离的原代肌细胞，其中敲除实验将测试特定HDAC3靶基因的要求，观察到的燃料选择和提高燃料效率的线粒体功能和跟踪代谢通量。独立后我未来的职业目标是破译骨骼肌对体育锻炼的兴奋反应背后的表观基因组机制。运动有益于健康的许多方面，特别是在肥胖和糖尿病的背景下。我的一般假设是，表观基因组机制的基础运动诱导有益的代谢重塑。我将使用全基因组方法和代谢组学方法全面描述运动引起的骨骼肌转录组和表观基因组变化。据我所知，这是第一奋进在全基因组范围内分析运动引起的表观基因组变化。这种无偏见的方法将产生全面的数据集，从数据挖掘和基序分析将产生新的假设，新的转录网络，响应运动。生物化学方法和代谢通量分析将被用来验证这些假设，其次是遗传动物模型和生理学研究的发展。总之，这些方法将产生由初步数据支持的可检验的假设，这对于成功竞争未来的资助机会至关重要。