Wound healing is a complex, dynamic process which is characterized by the actions of different cells, cytokines and the extracellular matrix. An important aspect of wound healing after surgical incision is the generation of wound strength, which is attributed to the deposition of type I collagen. Transforming growth factor beta (TGFbeta) is expressed early during wound healing and when applied exogenously, will accelerate wound repair. TGFbeta acts by stimulating type I collagen production and inhibiting interstitial collagenase production. Patients with cachexia who frequently require surgery for their underlying illnesses are at increased risk for surgery because of their poor wound healing ability. Many of the systemic affects of cachexia are attributed to elevated levels of tumor necrosis factor alpha (TNFalpha). In particular, TNFalpha might inhibit wound healing by inhibiting type I collagen production and stimulating interstitial collagenase production. Therefore, understanding the mechanisms of action of TGFbeta and TNFalpha and their complex interactions in the regulation of collagen metabolism might provide insights into normal tissue remodeling and the impaired wound healing of cachexia. Research performed under the present grant demonstrated that TNFalpha inhibits type I collagen gene transcription and stimulates collagenase gene transcription.
The Specific Aims of this proposal are: 1. To determine the mechanism by which TNFalpha inhibits type I collagen gene expression. 2. To determine the mechanism by which TNFalpha stimulates collagenase gene expression. 3. To elucidate the interactions between TGFbeta and TNFalpha on type I collagen and collagenase gene expression. The specific experiments proposed include the characterization of the TNFalpha inhibitory element in the type I collagen gene, an analysis of the phosphorylation of the transcription factor c-Jun by TNFalpha and the competition between TGFbeta and TNFalpha for activation of transcription through the AP-1 binding site, an inducible enhancer. By providing new knowledge on the regulation of collagen metabolism, this proposal will provide insight into the molecular pathogenesis of impaired wound healing during cachexia. New ideas on therapeutic interventions to accelerate wound healing might result from these investigations.
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