The form and function of the heart is determined by the large myocytes which comprise the majority of the volume of the myocardium and by the extracellular matrix (ECM). The cardiac fibroblast is the primary cell type involved in the dynamic regulation of the ECM and is also the dominant cell type in the myocardium accounting for approximately 90% of the cells. This proposal addresses the overall hypothesis that fibroblast function is regulated by the dynamic interaction between specific cell surface receptors (integrins), the intrinsic genetic regulation of the fibroblast and the structure of the ECM itself. The fibroblast undergoes phenotypic changes in response to physiological signals during development that result in changes in the composition and organization of the ECM. However, the mechanisms of how these phenotypic changes affect fibroblast function is not clear. In the proposed studies the investigators use isolated cardiac fibroblasts from different physiological stages (ages) to examine the overall hypothesis that the dynamic interaction between the ECM and the fibroblast is essential for the regulation of the fibroblast and consequently the organization and composition of the ECM. Specifically, it is hypothesized that the synthesis of collagen by cardiac fibroblasts is coordinated with the expression of MMPs and collagen specific integrins.
The specific aims of this proposal are to: 1) examine the expression of specific integrins, metalloproteases (MMP), and collagen in vivo during fetal, neonatal, and adult development; 2) examine these same parameters in vitro in cardiac fibroblasts isolated from the same physiological stages; 3) alter the expression of integrins, MMPs, and collagen synthesis in isolated fibroblasts by using antisense oligonucleotides and adenoviral transduction to determine the interaction of these 3 parameters; 4) determine the effect of mechanical stimulation on the expression and accumulation of integrins, collagens and MMPs of cardiac fibroblasts at different physiological stages; and 5) modify the structure of the ECM components in vitro to determine if abnormal ECM can affect the expression of integrins, MMPs and collagens. These studies will utilize a variety of morphological, biochemical and molecular techniques to analyze the dynamic interaction between the ECM and gene expression at several critical physiological stages that result in changes in the composition and organization of the ECM. However, the mechanisms of how these phenotypic changes affect fibroblast function is not clear. In the proposed studies, the investigators will use isolated fibroblasts from different physiological stages to examine the overall hypothesis that the dynamic interaction between the ECM and the fibroblast is critical to the transmission of mechanical and chemical signals which are essential for the regulation of ECM organization and composition during development. Specifically, it is hypothesized that the synthesis of collagen by cardiac fibroblasts is coordinated with the expression of MMPs and collagen specific integrins.
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