Fellowship for Bradford Blunt: Cardioprotective Effects of the Ras Interacting Protein Rlf

Recently, we became interested in and have NIH funding to investigate the role of the Ras effector protein Rlf in regulating the response of cardiomyocytes to hypertrophic agonists. Our research to date indicates that overexpression of Rlf in cardiomyocytes increases both basal and agonist stimulated activation of the PI3-kinase/Akt pathway. This effect appears to be coupled to protecting cardiomyocytes from the induction of apoptosis. Similarly, transgenic mice that overexpress Rlf in cardiac cells are protected from the apoptosis and fibrosis that results from chronic j3-agonist infusion. Determining the cellular mechanism and the physiologic significance of Rlf's cardioprotective effect is the focus of Brad's proposal. Although the proposed experiments are necessarily related to the ongoing NIH funded studies in my laboratory, Brad's preliminary results and proposed studies extend the focus of our currently funded studies to include the role of Rlf in regulating apoptosis and cardiomyocyte survival. His results have important implications in cardiac pathophysiology, particularly in the setting of ischemic injury. I have no doubt that the results of his proposed studies will greatly enhance our understanding of Rlf function in myocytes and will provide important mechanistic information regarding the regulation of cardiac survival.