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. .
Obesity, hypothyroidism and heart disease are major health concerns in today's society with significant health and economic consequences. The studies in this proposal provide mechanistic insight into a complex regulatory network that controls cardiac transcriptional reprograming and mitochondrial energetics. The current treatments for these diseases are often ineffective providing a need to develop new therapeutic targets.
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