Cardiac hypertrophy and heart failure are a growing medical and social problem. Current medical therapies are insufficient to repair the heart and merely postpone death. Cardiac hypertrophy is mediated by increased synthesis of specific proteins in cardiomyocytes. Although significant progress has been made in understanding hypertrophy-specific gene expression, it is now clear that protein expression levels do not always reflect the rate of transcription of the corresponding genes. The identification of mechanisms that regulate protein translation offers another critical strategy for treating disease by controlling protein synthesis of select proteins that directly underlie cardiac hypertrophy. In this proposal we will examine the role that BEX1 plays in the heart as a novel regulator of translational control during stress stimulation. We identified BEX1 as a factor that is upregulated in heart failure where it then interacts with molecules implicated in protein translation. We hypothesize that BEX1 is a novel regulator of cardiac hypertrophy and adaptation to stress through the translational control of selected proteins that are more proximally involved in the growth response. We will test our hypothesis by carrying out the following aims: (1) To determine the role of BEX1 in cardiac hypertrophy and transition to failure in vivo. (2) To determine the role of BEX1 in modulating the translation of specific mRNAs through association with RPL22 and RNA helicases DDX1 and DDX3x. (3) To identify the mRNAs that are controlled at a post-transcriptional level during hypertrophy, and the role of BEX1 in modulating this process. The initial part of the research proposal will be carried out in the lab of Dr. Jeffery Molkentin, a world-renowned cardiac researcher who studies cardiac hypertrophy using genetic mouse models. In this lab, I will address the in vivo role of BEX1 in the heart by using BEX1-null and BEX1- overexpressing mice and I will start addressing the mechanism by which BEX1 controls the translation of specific proteins. Importantly, in addition to elucidating the mechanism whereby BEX1 regulates translation after stress stimulation (aims 1 and 2), the current proposal will elucidate the uncoupling between transcription and translation in cardiomyocytes and will lead to the identification of those mRNAs that are differentially translated during hypertrophy (aim 3). Therefore, novel pathways and targeting mechanisms will be uncovered and will drive my independent research program for years to come.
Heart failure is a growing medical problem for which current medical therapies offer no cure. This proposal will uncover a novel mechanism of regulation of cardiac remodeling and function through identifying how the translation of specific maladaptive mRNAs is controlled during cardiac stress. The achievement of the proposed aims should open exciting new prospective and therapeutic possibilities.
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