Scleroderma or Systemic Sclerosis (SSc) is a disease of unknown etiology characterized by the excessive deposition of collagen and other connective tissue components in skin and multiple internal organs, prominent and often severe alterations in the microvasculature, and humoral and cellular immunologic abnormalities. Although the mechanisms involved in the pathogenesis of SSc are not completely known, it is clear that cutaneous, visceral, and vascular fibrosis is responsible for most of the clinical manifestations of the disease. It has been previously demonstrated that fibroblasts from affected SSc skin cultured in vitro produce excessive amounts of a variety of extracellular proteins. The exaggerated collagen production by SSc fibroblasts is the result of increased gene expression which largely results from higher transcription rates of various collagen genes. Despite the recent advances in the understanding of the regulation of collagen gene expression under normal conditions, very little has been learned regarding the intimate mechanisms responsible for the pathologic increase in the expression of collagen genes in SSc. We propose to examine the hypothesis that excessive production of collagen in SSc fibroblasts is due to alterations in the mechanisms that regulate the rates o transcription of collagen genes and involve abnormalities in the interactions of cis-regulatory elements present in the promoter and first intron of these genes with specific trans-acting DNA binding proteins. To test this hypothesis we will analyze sequences in the promoter and first intron of the alpha1(I) procollagen gene that are involved in the upregulation of its expression in SSc fibroblasts, identify DNA binding proteins that recognize specific regulatory elements within these regions of the gene, and perform a quantitative comparison between normal and SSc cells of the amounts of DNA binding proteins that interact with these regulatory elements. It is expected that the results from these studies will provide valuable clues towards the understanding of the pathogenesis of tissue fibrosis in SSc, and may provide novel avenues of investigation towards the development of therapeutic agents for this incurable disease.
Showing the most recent 10 out of 61 publications
