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

• 批准号: 8222523
• 负责人: ERIC N Olson
• 金额: $ 55.52万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/8222523
• 关键词: Adrenergic Agents; Biogenesis; Calcineurin; Cardiac; Cardiovascular system; Complex; Development; Diet; Disease; Energy Metabolism; Epidemic; Family; Foundations; Gene Expression; 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

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. PUBLIC HEALTH RELEVANCE: Dysregulation of cardiac metabolism and mitochondrial function is associated with obesity, type 2 diabetes, and heart failure, diseases with catastrophic cardiovascular outcomes. 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. By defining the mechanisms whereby MED13 controls metabolism and energy homeostasis, we will provide new insights into the regulation of muscle energy metabolism and offer novel therapeutic strategies for modulating these processes in the settings of heart and skeletal muscle disease.

描述（由申请人提供）：心脏需要高效代谢来维持收缩力和泵功能所需的ATP水平。心脏代谢异常与肥胖、2型糖尿病和心力衰竭有关，这些疾病是主要的健康流行病。核激素受体及其辅激活子和辅抑制子通过调节参与能量稳态和线粒体功能的基因的表达在控制能量代谢中起关键作用。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，通过与转录激活因子和抑制因子的结合作为控制基因表达的枢纽。我们已经发现，MED 13/Thrap 1是Mediator复合物的一种组分，作为心脏代谢的中心调节剂发挥作用，并且这样做会影响小鼠的心脏功能和代谢稳态。因此，MED 13的心脏表达升高增强心脏功能和代谢率并赋予对肥胖症的抵抗力，而心脏中MED 13缺乏导致心脏代谢减弱和对肥胖症的易感性。MED 13受microRNA 208和378负调控，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MED 13和调节它的microRNA控制代谢，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到的控制横纹肌代谢和功能的调控网络提供重要的新见解，并将通过介体-microRNA网络为代谢综合征和肌肉疾病的治疗调节提供机会。 公共卫生关系：心脏代谢和线粒体功能失调与肥胖、2型糖尿病和心力衰竭有关，这些疾病具有灾难性的心血管结局。我们已经发现，MED 13/Thrap 1是介体复合物的一种组分，作为心脏代谢的中心调节剂发挥作用，并且这样做会影响心脏功能和代谢稳态。通过定义MED 13控制代谢和能量稳态的机制，我们将为肌肉能量代谢的调节提供新的见解，并为在心脏和骨骼肌疾病的背景下调节这些过程提供新的治疗策略。