This is a request for an ADAMHA Research Scientist Development Award (RSDA). Three objectives are to be accomplished with this award: (1) expansion of an ongoing research program in alcoholic liver disease; (2) career development for the principal investigator in the areas of collaboration and mentoring; and (3) completion of experiments focusing on the pathophysiology of alcoholic liver injury and fibrosis. The applicant brings to the research program an in-depth understanding of hepatic fibrogenesis; dedication to the alcohol field is demonstrated by a clear and expanding focus on alcohol-induced liver disease. An RSDA will permit recruitment of young investigators to keep pace with new ideas. The research plan in this application addresses the mechanism underlying alcoholic liver fibrosis. As in all forms of fibrotic liver disease, lipocytes (hepatic stellate cells) play a prominent role; we hypothesize that in the setting of alcohol, lipocytes are activated to produce collagen by signals from an altered extracellular matrix. This postulate is based on observations that soluble mediators such as acetaldehyde, lipid aldehydes or TGFbeta, do not activate lipocytes in culture; cultured lipocytes activate readily, however, in response to changes in their surrounding extracellular matrix. This suggests that matrix alterations in vivo may lead to hepatic fibrosis. Inflammatory cells, particularly neutrophils, play an important role in our scheme of alcoholic liver fibrosis. Neutrophils migrate from the circulation to the liver by secreting extracellular matrix-degrading proteinases; we propose that in so doing, they provoke critical alterations in the hepatic perisinusoidal matrix that lead s to lipocyte activation. Neutrophil chemoattractants, produced by liver cells in the setting oc chronic ethanol ingestion, may contribute importantly to alcoholic fibrosis by stimulating neutrophil proteinase release. Interleukin-8 is a likely candidate, as preliminary studies implicate this chemokine in alcohol- induced liver injury. The studies proposed in this application fall logically into two categories. One focuses on the pathogenesis of """"""""alcoholic hepatitis"""""""" (neutrophil recruitment to the alcoholic liver); the other addresses the consequences of inflammatory cell activation (manifest as proteinase secretion) on lipocyte behavior. Via an RSDA, the applicant hopes to expand and split these aims into two independent research projects. The ultimate goal is to build a competitive research group that performs high- quality alcohol-related research.
