Type I collagen is the major component of connective tissue. Excessive accumulation of Type I collagen in the skin and internal organs is the hallmark of scleroderma, a progressive and currently incurable disease. The pathogenesis of scleroderma is not well understood. During the past 5 years, data generated from several lines of investigations have suggested that transforming growth factor-beta (TGF-beta) plays a critical role in the development of fibrosis in human diseases and experimental animal models. In scleroderma, elevated expression of TGF-beta has been demonstrated in affected tissues. We and others have shown that TGF-beta stimulates the synthesis of Types I, III, and VII collagens, and other components of the extracellular matrix. We have recently obtained evidence that the expression of the human alpha 1 Type I collagen gene (COL1A1) is increased by TGF-beta via a cis-acting element in the proximal promoter of the gene. The overall goal of the present project is to examine the molecular basis of stimulation of Type I collagen synthesis in normal human skin fibroblasts in response to TGF-beta.
In Specific Aim 1, cis- acting elements in human COL1A1 mediating responsiveness to TGF-beta will be identified and characterized by deletion analysis, mapping and functional studies.
In Specific Aim 2, the interaction of these putative regulatory elements with nuclear trans-acting proteins will be examined.
In Specific Aim 3, the genes coding for DNA-binding nuclear proteins which interact with TGF-beta-responsive elements in the COL1A1 promoter will be isolated from human fibroblast cDNA libraries. The positive clones will be sequenced and characterized. Understanding the molecular events involved in the stimulation of human COL1A1 expression by TGF-beta in this in vitro model will enhance our understanding of collagen gene regulation. These insights may lead to the development of specific agents which interfere with TGF-beta-induced collagen accumulation, and can be useful in the treatment of scleroderma.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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