During the growth and development of the heart, the components of the extracellular matrix (ECM) maintain a precise, 3-dimensional arrangement with collagen attaching near the Z band of myocytes. This arrangement of the ECM is intimately associated with cardiac function and alteration of these connections can result in abnormal growth and altered patterning. The principal cell surface receptors for the ECM are the members of the integrin family. However, the mechanism of how these integrin connections with the ECM change with growth is unknown. In response to pathophysiological signals cardiac myocytes undergo an increase in size (hypertrophy) or shape (dilation), the ECM:myocyte connection also must accommodate these changes. Cardiac fibroblasts also show adaptive changes in response to growth and developmental signals by altered collagen deposition, migration, and proliferation. Recent data has demonstrated that the integrin connections with the ECM shed their ectodomains during growth and development; however, the mechanism and function of this process is unknown. The proposed research will address the hypothesis that integrin shedding represents a method of altering receptor-ECM interaction which allows for changes in cell growth and phenotype and that the shed integrin ectodomain has a regulatory function on both cardiac fibroblasts and myocytes.
The specific aims that will addresses this hypothesis are to: 1) determine which specific integrins are being shed; 2) determine the mechanism responsible for shedding; and 3) determine the potential function of the shed integrin ectodomain, To address these specific aims, a variety of cell and molecular techniques in both in vivo and in vitro models of cardiac hypertrophy and dilation will be used. Preliminary data indicates that the enzymes responsible for the shedding are likely to be members of the Matrix Metalloprotease (MMP) family or A Disintegrin And Metalloprotease (ADAM) family. Specific inhibitors will be used to determine which of the specific MMPs or ADAMS are involved in the shedding process. A variety of biochemical and cell behavior assays including regulation of receptor number, collagen synthesis, cell migration and collagen gel contraction will be used to determine potential functions of the shed fragment on cardiac myocytes and fibroblasts. The proposed studies will provide fundamentally new information on the dynamic interaction of integrins, ECM and regulation of cardiac growth and development.
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