Regression of cardiac hypertrophy

描述(申请人提供)：由瓣膜或高血压性心脏病引起的压力超负荷引起的心肌肥厚是美国充血性心力衰竭最常见的原因之一。在过去的十年中，许多努力都集中在阐明介导心肌细胞对各种肥厚刺激的复杂反应以及从心肌肥厚到心力衰竭的进展的信号通路。似乎没有一条单一的途径可以单独调节心肌肥厚。相反，似乎更有可能的是，每条通路都是作为一个精心编排的肥大网络的组成部分运作的。近年来，人们发现了潜在的抗肥大和抑制反馈信号通路。加强这些负调控因子，而不是抑制正调控因子，可能是一种可行的抗肥厚策略。在这些基因中，Eya2(眼睛缺失2个同源基因)尤其令人感兴趣。我们建议进一步研究心脏中Eya2活性的分子机制，包括识别受Eya2影响的下游信号通路。这项研究将在众多肥大和抗肥厚信号通路之间的交叉对话的背景下揭示新的信号通路。因此，我们提出了以下具体目标：特定目的1：定义Eya2的直接转录靶点。特异性目的2：明确Eya2在心脏代谢中的作用。具体目的3：定义Eya2过度表达和抑制的生理后果。解剖支持Eya2活性的分子通路有可能确定治疗心力衰竭的新策略。公共卫生相关性：在美国，心肌肥大和随之而来的心力衰竭是发病率和死亡率的主要原因，每年造成30多万人死亡。这项拨款申请中提出的工作采用了一种新的方法，专注于积极参与逆转肥厚的新基因。了解这些新的和特定的信号通路的作用，将膜水平的事件与肥厚逆转联系起来，将有助于确定未来治疗努力的靶点。

DESCRIPTION (provided by applicant): Pressure overload-induced cardiac hypertrophy due to valvular or hypertensive heart diseases is one of the most common causes of congestive heart failure in the U.S. During the last decade, many efforts have been focused on the elucidation of the signaling pathways mediating the complex response of cardiomyocytes to various hypertrophic stimuli and the progression from cardiac hypertrophy to heart failure. No single pathway seems to regulate cardiac hypertrophy alone. Rather, it appears more likely that each pathway operates as a component of an orchestrated hypertrophic network. In recent years, potential anti-hypertrophic and inhibitory feedback signaling pathways have been discovered. Augmenting these negative regulators, rather than inhibiting the positive regulators, may be a viable anti-hypertrophic strategy. Among these genes, Eya2 (eyes absent 2 homolog) was of particular interest. We propose to further characterize molecular mechanisms underlying the Eya2 activity in hearts, including identification of down-stream signaling pathways affected by Eya2. This study will reveal novel signaling pathways in the context of cross talks between numerous hypertrophic and anti-hypertrophic signaling pathways. We therefore propose the following specific aims: SPECIFIC AIM 1: Define the direct transcriptional targets of Eya2. SPECIFIC AIM 2: Define the role of Eya2 in cardiac metabolism. SPECIFIC AIM 3: Define the physiological consequences of Eya2 overexpression and inhibition. Dissecting the molecular pathways underpinning Eya2 activity has the potential of identifying novel strategies for the treatment of heart failure. PUBLIC HEALTH RELEVANCE: Cardiac hypertrophy and ensuing heart failure are major causes of morbidity and mortality in the United States accounting for in excess of 300,000 deaths per year. The work proposed in this grant application takes a novel approach of focusing on novel genes that are actively involved in the reversal of hypertrophy. An understanding of the role of these novel and specific signaling pathways linking events at the level of the membranes to the reversal of hypertrophy would help identify targets for future therapeutic efforts.