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: 8963478
• 负责人: Chad E Grueter
• 金额: $ 37.91万
• 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/8963478
• 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; Hypothyroidism; In Vitro; Invertebrates; Link; Mammals; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Myocardial dysfunction; Nodal; Nuclear Receptors; Obesity; Outcome; 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; Transcriptional Regulation; Translating; base; cofactor; design; health economics; heart function; heart metabolism; in vitro Model; in vivo; insight; loss of function; member; metabolomics; mitochondrial dysfunction; new therapeutic target; obesogenic; overexpression; programs; research study; 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（由申请人提供）：肥胖已成为当今社会的主要流行病。它是心脏病的一个主要危险因素，有必要进行研究，以提高我们对肥胖症转录适应中所涉及的分子途径的理解，这些分子途径可能会转化为治疗靶点。肥胖的一个促成因素是甲状腺功能减退。肥胖对心脏的许多混杂影响与甲状腺功能减退症的影响重叠，包括线粒体功能障碍、心脏能量紊乱和最终心肌收缩力降低。心脏需要高效的新陈代谢来维持收缩力和泵功能所需的ATP水平。我们通过MED13鉴定了心脏中转录调节的信号通路，并发现该通路在调节能量稳态中起关键作用。我们对这一提议的初步研究表明，通过MED13改变心脏转录显著改变代谢基因表达，代谢产物产生和心脏功能，促使我们开发必要的工具来确定MED13在体外和体内的功能机制。本申请的目的是解读MED13依赖性转录调节心脏重编程响应肥胖和甲状腺激素水平改变的生理作用。我们假设MED13的功能是抑制肥胖和甲状腺功能减退症患者的心脏转录重编程。设计使用MED13功能获得和丧失小鼠来测试该假设的具体目的是：目的1：分析MED13调节心脏能量学响应肥胖的分子机制作用。计划的实验将测试MED13整合心脏中的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调控的关键信号通路的变化。目的2：确定慢性甲状腺功能减退症时心脏重构的MED13依赖性调节。所提出的实验旨在检验MED13抑制慢性甲状腺功能减退症应答中的转录重编程的假设。我们将利用与目标1相似的实验方法，在体外和体内解剖TH信号转导的MED13依赖性心脏效应。这些研究将为肥胖和甲状腺功能减退症中心脏重编程的调节网络提供机制性的见解。新的见解将为心脏疾病的治疗调节提供机会，这些心脏疾病具有破坏的转录编程，改变的心脏能量学和功能降低。.