Regression of cardiac hypertrophy

描述（由申请人提供）：由于瓣膜或高血压心脏病引起的压力超负荷诱导的心脏肥大是美国充血性心力衰竭的最常见原因之一。在过去十年中，许多努力集中在阐明介导心肌细胞对各种肥大刺激的复杂反应的信号传导途径以及从心脏肥大到心力衰竭的进展。似乎没有单一的途径单独调节心脏肥大。相反，似乎更有可能的是，每个通路都是一个精心策划的肥大网络的组成部分。近年来，人们发现了潜在的抗肥大和抑制性反馈信号通路。增强这些负调节因子，而不是抑制正调节因子，可能是一种可行的抗肥大策略。在这些基因中，Eya2（眼睛缺失2同源物）是特别感兴趣的。我们建议进一步表征心脏中Eya 2活性的分子机制，包括鉴定受Eya 2影响的下游信号通路。这项研究将在众多肥大和抗肥大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，我们提出以下具体目标：具体目标1：确定Eya 2的直接转录靶点。具体目标2：明确Eya 2在心脏代谢中的作用。具体目标3：明确Eya 2过表达和抑制的生理后果。剖析支撑Eya 2活性的分子途径具有确定治疗心力衰竭的新策略的潜力。公共卫生相关性：心脏肥大和随后的心力衰竭是美国发病率和死亡率的主要原因，每年造成超过300，000人死亡。在这项拨款申请中提出的工作采取了一种新的方法，专注于积极参与逆转肥大的新基因。了解这些新的和特定的信号通路的作用，在膜的水平上连接事件的逆转肥大将有助于确定未来的治疗工作的目标。

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.