Fellowship Rebecca Scotland: Role of Rlf in Regulating Cardiac Function

Chronic cardiac stress associated with systemic hypertension or ischemic heart disease results in an initial phase where heart cells hypertrophy to accommodate for an increased workload (compensated hypertrophy) but often this response progresses to a stage in whiGhthe enlarged cells no longer function properly (decompensated hypertrophy). Studies show that the small monomeric G-protein, Ras, plays an important role in the organization of heart cell fibers and in regulating gene expression and growth of cardiac cells. Ras mediates these effects by modulating different signaling pathways. In our preliminary studies using neonatal rat ventricular myocytes, a commonly used cell model to study cardiac cell signaling, we found that the Ras interacting protein, Ral-GDS like factor (Rlf), blunted the Ras-induced activation of JNK, a MAPK family member implicated in decompensated cardiac responses. In contrast, Rlf does not block Ras-mediated activation of ERK or Akt, kinases previously associated with a compensatory hypertrophic response. Therefore, Rlf may play an important role in the transition from initial compensated phase to a decompensated stage of cardiac hypertrophy. I hypothesize that increased Rlf expression modulates cardiac signaling and preserves cardiac function following exposure to hypertrophic agonist. To test this hypothesis, I will determine the consequences of cardiac specific overexpressiol1 of Rlf in transgenic mice on the activation of kinases associated with regulating cardiomyocyte growth and survival (JNK, ERK, Akt) and on the development of cardiac hypertrophy following chronic beta-adrenergic stimulation in vivo.