We propose the establishment of a SCOR on the Pathogenesis of Scleroderma (SSc) at the University of Tennessee, Memphis. This application brings together a diverse and highly talented group of biomedical scientific investigators with a remarkable history of scientific collaborations and accomplishments in research related to SSc whose attention has now been focused on selected aspects of the biology of the collagenous matrix in SSc which are 1) collagen-induced outgrowth of fibroblast-like cells from cultures of SSc peripheral blood mononuclear cells (PBMC), 2) refractoriness of matrix metalloproteinase (MMP)-1 in SSc lesional fibroblasts to upregulation by cytokines, and 3) collagen-induced platelet aggregation. Project #1 will characterize mechanisms by which type I collagen (CI) induces the outgrowth of FLC from PBMC, a potentially extremely important mechanism by which collagen-producing fibroblasts populate tissues and organs involved in fibrogenesis of SSc. Project #2 addresses the pervasive problem of an inherent resistance of MMP-1 upregulation in lesional SSc fibroblasts by cytokines such as IL-1, TNFalpha, and bFGF. This dysregulation of MMP-1 likely contributes to fibrosis in SSc by leading to decreased removal of collagen in sites where it is being produced. Project #3 will clone and perform functional studies on platelet CI and CIII receptors (R) and will develop blocking peptides that may prove therapeutically useful in halting excessive CI and CIII induced platelet aggregation in SSc patients. An Administrative Core and Molecular Resources Core Laboratory will support the three projects of the SCOR, providing administrative oversight and necessary assistance to each SCOR project. This SCOR will provide a vehicle through which a highly synergistic multidisciplinary approach can be focused on SSc. The spirit of cooperation and collaboration that has been the hallmark over the years of the members of the UT-VAMC Connective Tissue Research Group combined with the commitment of the University of Tennessee, Memphis to this SCOR will assure a successful and expeditious attaining of its goal.
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