The goals of this research project have evolved over its eighteen years of existence. The initial goal was to understand the mechanisms by which TNFalpha inhibit the wound healing response in Cachexia patients, and utilized animal models over-expressing TNFalpha to study the wound healing response in vivo. Based on the advances from our laboratory over others, the research has evolved into more mechanistic studies to determine molecular mechanisms by which TNFalpha inhibits fibrosis by examining intracellular signal transduction and gene expression. As suggested by the reviewers and approved by the NIH grant administration, we have now changed the title of this proposal to reflect its evolution to the new title """"""""Molecular Mechanisms by which TNFalpha Inhibits Fibrosis"""""""". The underlying hypothesis that we have made to pursue this research program are now explicitly stated and include: 1. The mechanisms by which TNFa inhibits fibrosis can be investigated by studying the regulation of Type I collagen in cultures of fibrogenic cells. 2. Cultures of primary fibrogenic cells more closely approximate the in vivo conditions of fibrosis than immortal cell lines. 3. Two key mechanisms by which TNFalpha inhibits fibrosis are by decreasing collagen mRNA levels and by inducing apoptosis in fibrogenic cells. 4. Comparing two fibrogenic cell types, fibroblasts and hepatic stellate cells, generalizations about wound healing and fibrosis and the inhibitory effects of TNFalpha.
The specific aims of the proposal are: 1. To determine the effect of TNFalpha on collagen a1 (I) mRNA stability. 2. To assess the regulation of alphaCP by TNFalpha. 3. To assess the role of JNK in TNFalpha induced apoptosis. 4. To assess the effect of TNFalpha on reactive oxygen species and mitochondrial permeability transition.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Ikeda, Richard A
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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