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.
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.
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