Cardiac hypertrophy and cardiomyopathy are critical events in the onset of heart failure. The identification of specific pathways which activate defined contractile, electrophysiological, myocyte growth, and cardiac cell survival responses of the hypertrophied and failing heart is critical for development of biologically targeted therapy. Recent studies have implicated a pivotal role for biomechanical and hormonal signals from the extracellular matrix, cardiac cytokine and G protein coupled receptors, cardiac cytoskeletal pathways, and downstream intracellular kinases. Accordingly, the central objective of the present project is to identify intersecting molecular pathways that trigger important features of cardiac hypertrophy, cardiomyopathy, and the transition of heart failure. The program will capitalize on germline and somatic gene modifications in unique genetically engineered model systems, incorporating a spectrum of physiological assays for specific functional phenotypes in living animals, intact muscle, and single cells. The program will explore the role of cytoskeletal signaling pathways that emanate from focal adhesion complexes, a newly described MLP-telethonin complex, and a novel LIM domain protein (FHLI/SLIM1). Mechanistic links between these signaling pathways for hypertrophy and cardiomyopathy and myocyte survival pathways will be examined in relation to a new stress-inducible negative regulator of gp130 cytokines (SOCS 3). Biomechanical stretch and hormonal induced pathways for hypertrophy will be directly examined in both in vitro and in vivo systems, with a focus on integrins, novel G protein coupled receptors, and CAM kinase. The program integrates the independent expertise of the three project leaders in genetically engineered mouse models of human cardiac disease (K. Chien), the molecular pharmacology of cardiac signals for hypertrophy (J. Brown), and cardiovascular bioengineering technology and computational modeling of biomechanical stress responses during cardiac remodeling (A. McCulloch). The Program will integrate state-of-the-art technology via our Myocardial Cell Biology and Viral Vector Core A (K. Knowlton/S. Evans), Transgenic and Gene Targeted Mouse Core B (J. Chen/K. Chien), and Animal Physiology and In Vivo Gene Transfer Core C (J. Ross). The long history of collaboration amongst the Program investigators should lead to new therapeutic insights.
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