- The principal investigator's long-term objective is to understand the regulation of ECM production by human fibroblasts and its dysregulation in fibrotic diseases such as scleroderma (SSc). Substantial evidence has accumulated in recent years that implicates transcriptional activation of collagen genes as a key component in development of fibrosis in SSc and other fibrotic diseases. Lesional SSc fibroblasts maintain an activated phenotype during propagation in culture, thus providing an accessible system to study the molecular mechanisms responsible for the elevated expression of collagen genes. Data generated during the last funding period together with work by others reveal that SSc and normal fibroblasts respond differently to exogenous signals transmitted by cytokines as well as integrins. In addition, the principal investigator has recently identified transcription factors Sp1 and Sp3 as central regulators of the COL1A2 gene transcription. More importantly, the principal investigator has shown that Sp1 and Sp3 not only contribute to the basal expression level but can elicit inductive responses to serum and at least one cytokine, Oncostatin M. These results enable the principal investigator to propose a much more complete model for collagen gene regulation, in which intersecting cytokine and integrin signaling pathways exert induction or repression effects through a limited number of transcription factors. Dysregulated response to these signaling pathways likely underlies the elevated levels of collagen gene expression in SSc. This model thus provides the basis for unraveling the complex molecular mechanism responsible for abnormal regulation of collagen genes in SSc fibroblast.
Four specific aims are proposed: 1) To identify the cis-regulatory elements and to characterize levels and activities of the cognate transcription factors in the COL1A2 promoter responsible for the different regulation of basal and cytokine (TGF-beta, OSM) stimulated collagen gene transcription in SSc and normal fibroblasts; 2) to characterize cis-regulatory elements in the human COL1A2 promoter mediating integrin modulation of the collagen gene transcription in SSc and normal fibroblasts; 3) to identify and characterize additional trans-acting factors involved in regulation of the human COL1A2 promoter activity, and 4) to characterize intracellular signaling pathways mediating cytokine and integrin regulation of collagen production in SSc and normal fibroblasts.
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