Deciphering a Regulatory Circuit for Myocardial Metabolism and Energy Homeostasis

破译心肌代谢和能量稳态的调节回路

基本信息

批准号：
8764734
负责人：
ERIC N Olson
金额：
$ 61.97万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764734
关键词：
Adrenergic Agents Biogenesis Calcineurin Cardiac Cardiovascular system Complex Development Diet Disease Energy Metabolism Epidemic Family Foundations Gene Expression Gene Expression Profiling Genes Goals Health Heart Heart Diseases Heart failure Homeostasis Introns Knockout Mice Link Mediating Mediator of activation protein Metabolic Metabolic syndrome Metabolism MicroRNAs Mitochondria Multiprotein Complexes Mus Muscle Muscle function Myocardial Myocardium Myopathy Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nuclear Receptors Obesity Outcome Peroxisome Proliferator-Activated Receptors Physiological Play Predisposition Process Pump Regulation Resistance Role Signal Transduction Skeletal Muscle Stimulus Stress Striated Muscles Therapeutic Thyroid Hormones Transcription Coactivator Transcription Repressor/Corepressor Transcriptional Regulation Transgenic Mice adrenergic base heart metabolism insight loss of function metabolic rate muscle metabolism novel therapeutics pressure research study therapeutic development

项目摘要

DESCRIPTION (provided by applicant): The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function. Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure, which represent major health epidemics. Nuclear hormone receptors and their coactivators and corepressors play critical roles in the control of energy metabolism by regulating the expression of genes involved in energy homeostasis and mitochondrial function. Transcriptional control by nuclear hormone receptors is mediated by the Mediator, a large multiprotein complex that functions as a hub to control gene expression through association with transcriptional activators and repressors. We have discovered that MED13/Thrap1, a component of the Mediator complex, functions as a central regulator of cardiac metabolism and, in so doing, influences cardiac function and metabolic homeostasis in mice. Thus, elevated cardiac expression of MED13 enhances cardiac function and metabolic rate and confers resistance to obesity, whereas MED13 deficiency in the heart causes diminished cardiac metabolism and susceptibility to obesity. MED13 is negatively regulated by microRNAs 208 and 378, which control stress-dependent cardiac remodeling and metabolism. The overall goals of this project are to define the precise mechanisms whereby MED13 and the microRNAs that regulate it control metabolism, energy homeostasis, mitochondrial biogenesis, cardiac stress-responsiveness and phenotypic switching of cardiac and skeletal muscles. These studies will provide important new insights into a previously unrecognized regulatory network for the control of striated muscle metabolism and function, and will open opportunities for therapeutic modulation of metabolic syndromes and muscle diseases through the Mediator-microRNA network.

描述（由申请人提供）：心脏需要高效的代谢来维持收缩性和泵功能所需的ATP水平。异常心脏代谢与肥胖，2型糖尿病和心力衰竭有关，这代表了主要的健康流行病。核激素受体及其共激活因子和核压剂通过调节与能量稳态和线粒体功能有关的基因的表达来控制能量代谢中的关键作用。核激素受体的转录控制是由介体介导的，介体是一种大型多蛋白复合物，它是通过与转录激活剂和阻遏物缔合控制基因表达的中心。我们发现，介体复合物的组成部分Med13/thrap1是心脏代谢的中心调节剂，并且这样做会影响小鼠的心脏功能和代谢稳态。因此，MED13的心脏表达升高会增强心脏功能和代谢率，并赋予对肥胖症的抵抗力，而心脏的MED13缺乏会导致心脏代谢降低和对肥胖症的敏感性。 MED13受microRNA 208和378负调节，这些microRNA和378控制应力依赖性心脏重塑和代谢。该项目的总体目标是确定MED13和调节IT控制代谢，能量稳态，线粒体生物发生，心脏应激反应性和心脏和骨骼肌表型切换的精确机制。这些研究将为以前未被认可的调节网络提供重要的新见解，以控制横纹的肌肉代谢和功能，并通过调解员网络为新陈代谢综合症和肌肉疾病的治疗调节开放机会。