Scleroderma (diffuse systemic sclerosis) is a poorly understood systemic disease that universally involves cutaneous fibrosis in the early stage. There is no known etiology or effective treatment for this disease. The objective of this proposal is to characterize the role of a recently described fibrotic growth factor, fibrosin, in the pathogenesis of scleroderma. Fibrosin was initially described as a T-cell derived liver fibrotic factor. Preliminary data suggest that fibrosin is also involved in the maintenance of cutaneous fibrosis in scleroderma skin. Our hypothesis is that fibrosin factions in a dysregulated autocrine loop in scleroderma dermal fibroblasts to induce prolonged overexpression of collagen. The long-range objectives are to identify potential targets to develop new therapies for this devastating disease. A series of three interrelated specific aims will examine (1) tissue levels and localization of fibrosin expression in normal versus skin from scleroderma patients; (2) the regulation of collagen and fibrosin production in dermal fibroblasts from normal versus scleroderma patients in vitro; and (3) potential cell sources of fibrosin in patients with scleroderma. Fibrosin levels will be assess by several techniques. Semi-quantitative RT-PCR using a competitor construct along with in situ hybridization will be used to assess mRNA transcripts. Polyclonal and monoclonal antibodies will be used to identify protein and to neutralize fibrosin in functional assays. These experiments will establish whether fibrosin plays a pathologic role in the overproduction of extracellular matrix in scleroderma.
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