MED13 regulation of cardiac transcription in obesity and hypothyroidism

MED13 对肥胖和甲状腺功能减退症心脏转录的调节

• 批准号: 9172203
• 负责人: Chad E Grueter
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172203
• 关键词: Agonist; Biogenesis; Cardiac; Chronic; Clinical; Complex; Cues; Data; Defect; Diet; Disease; Energy Metabolism; Epidemic; Event; Exhibits; Foundations; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Health; Heart; Heart Diseases; High Fat Diet; Homeostasis; Hormone Responsive; Hypothyroidism; In Vitro; Invertebrates; Link; Mammals; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Myocardial dysfunction; Nodal; Nuclear Receptors; Obesity; Outcome; Pathologic; Pathology; Pathway interactions; Pharmacological Treatment; Phosphotransferases; Physiological; Play; Predisposition; Production; Publishing; Pump; RNA Polymerase II; Regulation; Research; Resistance; Respiratory physiology; Risk Factors; Role; Signal Pathway; Signal Transduction; Societies; Solid; Stress; Testing; Therapeutic; Thyroid Hormone Receptor; Thyroid Hormones; Transcription Regulation Pathway; Transcriptional Regulation; Translating; base; cofactor; design; experimental study; health economics; heart function; heart metabolism; in vitro Model; in vivo; insight; loss of function; member; metabolomics; mitochondrial dysfunction; new therapeutic target; obesity treatment; obesogenic; overexpression; programs; public health relevance; response; therapeutic target; tool

DESCRIPTION (provided by applicant): Obesity has become a major epidemic in today's society. It is a major risk factor for cardiac disease and necessitates studies that enhance our understanding of the molecular pathways involved in transcriptional adaptation to obesity that could potentially translate into therapeutic targets. A contributing factor in obesity is hypothyroidism. Many of the confounding cardiac effects of obesity overlap with effects of hypothyroidism including mitochondrial dysfunction, disrupted cardiac energetics, and ultimately decreased cardiac contractility. The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function. We identified a signaling pathway for transcriptional regulation in the heart by MED13 and found that this pathway plays a key role in modulating energy homeostasis. Our preliminary studies for this proposal show that altering cardiac transcription by MED13 significantly alters metabolic gene expression, metabolite production and cardiac function, prompting us to develop the necessary tools to identify the mechanism for MED13 function in vitro and in vivo. The objective of this application is to decipher the physiological role of MED13-dependent transcriptional regulation of cardiac reprograming in response to obesity and altered thyroid hormone levels. We hypothesize that MED13 functions to inhibit cardiac transcriptional reprogramming in obesity and hypothyroidism. The specific Aims designed to test this hypothesis using MED13 gain- and loss-of-function mice are: Aim 1: To analyze the molecular mechanistic action for MED13 regulation of cardiac energetics in response to obesity. The experiments planned will test the hypothesis that MED13 integrates metabolic signaling events in the heart, functioning as a brake to regulate transcriptional reprogramming. We will utilize in vivo and in vitro models of obesity to assess changes in cardiac gene expression, mitochondrial function, metabolomics profile and key signaling pathways that are regulated by MED13. Aim 2: To define MED13- dependent regulation of cardiac remodeling in response to chronic hypothyroidism. The proposed experiments are designed to test the hypothesis that MED13 suppresses transcriptional reprograming in response to chronic hypothyroidism. We will utilize a similar experimental approach as in Aim 1 to dissect MED13-dependent cardiac effects of TH signaling in vitro and in vivo. These studies will provide mechanistic insights into the regulatory network linking cardiac reprograming in obesity and hypothyroidism. The new insights will provide opportunities for therapeutic modulation of cardiac diseases with disrupted transcriptional programing, altered cardiac energetics and decreased function. .

描述(申请人提供)：肥胖已成为当今社会的一种主要流行病。它是心脏病的一个主要风险因素，需要进行研究，以增强我们对肥胖转录适应的分子途径的理解，这些分子途径可能转化为治疗靶点。导致肥胖的一个因素是甲状腺功能减退。肥胖的许多令人困惑的心脏影响与甲状腺功能减退的影响重叠，包括线粒体功能障碍、心脏能量学紊乱，并最终降低心脏收缩能力。心脏需要高效的新陈代谢来维持收缩和泵功能所需的三磷酸腺苷水平。我们通过MED13确定了心脏转录调控的信号通路，并发现该通路在调节能量平衡方面起着关键作用。我们对这一提议的初步研究表明，MED13改变心脏转录显著改变代谢基因的表达、代谢产物的产生和心脏功能，促使我们开发必要的工具来确定MED13在体外和体内的作用机制。这项应用的目的是破译MED13依赖的心脏重编程转录调节在肥胖和甲状腺激素水平变化中的生理作用。我们假设MED13在肥胖和甲状腺功能减退症中起抑制心脏转录重编程的作用。利用MED13获得和丧失功能的小鼠来验证这一假说的具体目的是：目标1：分析MED13调节心脏能量学对肥胖反应的分子机制作用。计划中的实验将检验这一假设，即MED13整合了心脏中的代谢信号事件，起到调节转录重新编程的刹车的作用。我们将利用体内和体外肥胖模型来评估心脏基因表达、线粒体功能、代谢组学和MED13调控的关键信号通路的变化。目的2：明确慢性甲状腺功能减退时心脏重构的MED13依赖性调节。拟议的实验旨在测试MED13抑制转录重编程以应对慢性甲状腺功能减退的假设。我们将利用与目标1类似的实验方法，在体外和体内剖析TH信号对MED13依赖的心脏效应。这些研究将为肥胖症和甲状腺功能减退症的心脏再编程之间的调节网络提供机械性的见解。这些新的见解将为转录程序中断、心脏能量学改变和功能下降的心脏病的治疗调整提供机会。。