The underlying hypothesis of this proposal is that the impaired wound healing that occurs in patients with cachexia results from the profound effects of excessive tumor necrosis factor alpha (TNFa) on extracellular matrix proteins. TNFa is known to inhibit fibrillar collagen expression and to stimulate interstitial collagenase (MMP-1) expression. TNFa is a potent activator of the stress activated protein kinase (SAPK/JNK), an activator of c-JUN that in turn is the principal transcription factor stimulating the collagenase gene.
The aims of this proposal are: 1) To determine which TNFa receptor is responsible for the upregulation of collagenase and the downregulation of collagen. 2) To determine the role of ceramide in the stimulation of SAPK/JNK by TNFa. 3) To determine the intermediate steps by which TNFa activates SAPK/JNK. 4) To determine the signal transduction pathway by which TNFa inhibits type I collagen gene expression. 5) To assess potential inhibitors of TNFa signal transduction. Most of the experiments will use cultures of normal human fibroblasts, but selected experiments will involve use of mouse fibroblasts for the purpose of establishing stable transfectants. HL-60 cells will be used to examine the role of ceramide in regulating the extracellular matrix.
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