Cardiac hypertrophy is an adaptive mechanism that results in individual cardiac myocyte enlargement. A wide variety of stimuli induce hypertrophy with varying consequences. Exercise causes cardiac hypertrophy that is beneficial and compensatory, whereas, pathologic hypertrophy is maladaptive and a leading predictor of heart failure. The ability of cardiac myocytes to hypertrophy is a result of the activation of various intracellular factors and signaling cascades. These pathways are involved in both physiologic and pathologic hypertrophy. The goal of this fellowship is to delineate the pathways that are distinctly activated depending on the specific stimuli. The emphasis of the proposal involves the use of transgenic mice models to characterize the signaling processes Initially, the cardiac phenotype of a transgenic line expressing a constitutively active glycogen synthase kinase-3 (GSK-3) will be characterized in response to physiologic and pathologic hypertrophic stimuli. Additionally, the transgenic GSK-3 mice will be crossed with several transgenic models of hyertrophic cardiomyopathy (HCM) that contain specific mutations in cardiac sarcomeric proteins. These mice include a mutation in the actin-binding domain of the murin alpha-myosin heavy chain (alpha-MHC), and both a missense mutation and a truncated molecule of cardiac troponin T (cTnT). These crossed animals will be analyzed to determine the contribution of the GSK-3 cascade in the phenotypes of HCM.
| Luckey, Stephen W; Walker, Lori A; Smyth, Tyson et al. (2009) The role of Akt/GSK-3beta signaling in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 46:739-47 |
| Luckey, Stephen W; Mansoori, Jason; Fair, Kelly et al. (2007) Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males. Am J Physiol Heart Circ Physiol 292:H838-45 |
| Konhilas, John P; Watson, Peter A; Maass, Alexander et al. (2006) Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ Res 98:540-8 |
| Konhilas, John P; Maass, Alexander H; Luckey, Stephen W et al. (2004) Sex modifies exercise and cardiac adaptation in mice. Am J Physiol Heart Circ Physiol 287:H2768-76 |
