MED13 regulation of cardiac transcription in obesity and hypothyroidism

描述（由申请人提供）：肥胖已成为当今社会的一大流行病。它是心脏病的一个主要危险因素，因此有必要进行研究，以增强我们对肥胖转录适应的分子途径的理解，从而有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。肥胖的许多混淆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，心脏能量供应中断，最终心脏收缩力下降。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。我们确定了MED13在心脏中转录调控的信号通路，并发现该通路在调节能量稳态中起关键作用。我们的初步研究表明，通过MED13改变心脏转录会显著改变代谢基因的表达、代谢物的产生和心脏功能，这促使我们开发必要的工具来识别MED13在体外和体内的功能机制。本应用程序的目的是破译med13依赖性转录调节心脏重编程的生理作用，以应对肥胖和甲状腺激素水平改变。我们假设MED13在肥胖和甲状腺功能减退中具有抑制心脏转录重编程的功能。使用MED13功能获得和功能丧失小鼠来验证这一假设的具体目的是：目的1：分析MED13在肥胖反应中调节心脏能量学的分子机制。计划中的实验将测试MED13整合心脏代谢信号事件的假设，作为调节转录重编程的制动器。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、代谢组学特征和MED13调节的关键信号通路的变化。目的2：明确慢性甲状腺功能减退患者心脏重构的MED13依赖性调控。所提出的实验旨在验证MED13在慢性甲状腺功能减退症中抑制转录重编程的假设。我们将采用与Aim 1中类似的实验方法，在体外和体内解剖TH信号对med13依赖性心脏的影响。这些研究将为肥胖和甲状腺功能减退的心脏重编程调控网络提供机制见解。这一新发现将为转录编程中断、心脏能量学改变和功能下降的心脏疾病的治疗调节提供机会。

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. .