verbatim): The extracellular matrix and cytoskeleton are important in determining the function of the myocardium. Integrins are cell surface adhesive molecules, mechanotransduers, and transmit signals bi-directionally across the cell membrane, linking the extracellular matrix to the cytoskeleton. Beta-1 integrins are important components of hypertrophic signaling pathways and also in part determine normal cardiac function. The primary hypothesis of the current proposal is that beta-1 integrin expression and signaling influence growth and survival of the cardiac cell. To test this hypothesis, the following specific aims are proposed: 1) To assess the role of three alphabeta-1 integrin heterodimers and an integrin binding protein, in the hypertrophic and apoptotic responses of cultured ventricular myocytes. For these experiments recombinant adenoviral expression vectors and well characterized cardiac cell culture models of hypertrophy and apoptosis will be used. 2) To determine if apoptosis is the primary mechanism through which decreased beta-1 integrin protein expression in the murine cardiac myocyte leads to progressive fibrosis and heart failure. Mice have been constructed where the beta-1 integrin gene is disrupted only cardiac myocytes. The mechanism that causes progressive fibrosis and evolution of heart failure in these animals will be investigated. 3) To evaluate the role of the striated-muscle specific isoform of beta-1 integrin, termed beta-1D, as compared to the ubiquitously expressed beta-1A isoform, in defining normal function of the mature murine heart. A transgenic rescue approach will be used to restore cardiac myocyte expression of beta-lA or beta-1D integrin in the integrin deficient animals discussed in aim 2. 4) Investigate the morphological characteristics, integrin expression profile and integrin related signaling events, as well as extracellular matrix production of beta-1 integrin null cardiac fibroblasts as compared to wild-type fibroblasts, and fibroblasts that express only the beta-1A or beta-1D integrin isoforms. Beta-1 integrin null cardiac fibroblasts have been derived from our """"""""floxed"""""""" mice. These cells will be characterized and then used to test the function of the ubiquitous (beta-1A) as compared to the striated muscle-specific (beta-1D) integrin isoforms. These studies will give us great insight into the function of beta-1A and beta-1D integrins in the normal and abnormal heart.
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