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：
8589000
负责人：
ERIC N Olson
金额：
$ 63.11万
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/8589000
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 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）：心脏需要高效的新陈代谢来维持收缩性和泵功能所需的 ATP 水平。心脏代谢异常与肥胖、2 型糖尿病和心力衰竭有关，这些都是主要的健康流行病。核激素受体及其共激活子和辅阻遏物通过调节参与能量稳态和线粒体功能的基因的表达，在能量代谢的控制中发挥关键作用。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，通过与转录激活剂和阻遏物结合，充当控制基因表达的中枢。我们发现 MED13/Thrap1 作为介体复合物的一个组成部分，作为心脏代谢的中央调节器发挥作用，从而影响小鼠的心脏功能和代谢稳态。因此，MED13的心脏表达升高可增强心脏功能和代谢率，并赋予对肥胖的抵抗力，而心脏中MED13的缺乏会导致心脏代谢减弱和对肥胖的易感性。 MED13 受到 microRNA 208 和 378 的负向调节，它们控制应激依赖性心脏重塑和代谢。该项目的总体目标是确定 MED13 和调节它的 microRNA 控制新陈代谢、能量稳态、线粒体生物发生、心脏应激反应以及心脏和骨骼肌表型转换的精确机制。这些研究将为以前未被认识的控制横纹肌代谢和功能的调节网络提供重要的新见解，并将为通过 Mediator-microRNA 网络治疗调节代谢综合征和肌肉疾病提供机会。