GROWTH CONTROL OF NORMAL AND CIRRHOTIC HEPATOCYTES

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The long-term goal of the principal investigator is to become an independently funded academic surgical scientist in the field of gastrointestinal surgery. A clinical investigator research program during surgical training provided a strong preliminary experience in large animal physiology studies. This proposal is designed to train the principal investigator as an academic surgical molecular biologist. This proposal includes didactic work, tutelage in cell culture and isolation and flow cytometry under Dr. Reid and experience in signal transduction, differential display PCR and gene expression under Dr. Brenner. Completion of this program will allow the principal investigator to become a clinical scientist with a focus of gastrointestinal surgery and molecular biology. UNC-Chapel Hill has a rich tradition of basic science research and programs such as the Center for Gastrointestinal Biology and Disease and the Program in Molecular Biology and Biotechnology. These programs provide expertise in molecular biology, immunoassay, biostatistics and didactic course work. The laboratory space and use of common laboratory equipment will be provided by Drs. Reid and Brenner. This proposal focuses on the growth control mechanisms of primary and cirrhotic hepatocytes in response to inhibition of the transcription factor nuclear factor kappa beta (NFkappaB). In vivo experiments demonstrated that NFkappaB is necessary to prevent hepatocyte apoptosis or G2/M cell cycle arrest in hepatocytes during hepatic regeneration. This proposal aims to determine if apoptosis or cell cycle arrest is the primary mechanism of growth control. In addition, differential display PCR will be used to identify novel genes involved with growth control in both normal hepatocytes and cirrhotic hepatocytes. Identification of novel or differentially regulated hepatocyte growth control genes may provide information about altered growth control of cirrhotic hepatocytes.