Cardiac hypertrophy is a critical adaptive physiological response of the heart, serving initially as a compensatory response, allowing adaptation to increased work demands or following injury. However, there can be a transition from cardiac hypertrophy to dysfunction, and, ultimately, overt failure. The signaling pathways which orchestrate various features of in vivo hypertrophy are largely unknown. In our previous Program, we identified a number of candidate signaling pathways which can activate specific features of the hypertrophic response in an in vitro model system. With recent advances in gene targeting technology, miniaturized physiological technology, and new approaches for obtaining tissue-specific or conditional knock-out of genes in the in vivo mouse heart, the current proposed Program is designed to allow the molecular dissection of the in vivo signaling pathways for specific phenotypic features of cardiac hypertrophy and the transition to dilated cardiomyopathy in the adult heart at multiple levels. Accordingly, the central scientific theme of the Program is to identify the nodal points in the signaling pathway which orchestrate specific features of the in vivo hypertrophic response. The program will focus on candidate signaling pathways, which extend from the membrane to the nucleus, utilizing a combination of in vitro and in vivo murine based model systems.
The Specific aims are three-fold: 1) to examine the role of gpl130 and retinoid-dependent signaling pathways in the activation of distinct features of the hypertrophic response; 2) to determine the role of specific mitogen- and Ca++ -activated kinases in the control of the cardiac hypertrophic response; 3) to examine the role of beta-adrenergic receptor uncoupling in the transition from stable to decompensated dilated cardiomyopathy. Four Core Units will allow the efficient implementation of state-of-the-art molecular, cellular, genetic, and physiological technology, much of which has been developed and/or adapted to cardiac systems at UCSD during our previous Program. This proposed Program should lead to the identification of molecular determinants of cardiac hypertrophy, as well a to the development of new approaches to assess signaling pathways for complex, in vivo adult cardiac phenotypes. In addition, these studies may eventually lead to new targets and strategies to blunt the hypertrophic response in the setting of the transition to overt heart failure.
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