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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002640-04
Application #
6524154
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$124,270
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Surgery
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Black, Dalliah; Lyman, Suzanne; Qian, Ting et al. (2007) Transforming growth factor beta mediates hepatocyte apoptosis through Smad3 generation of reactive oxygen species. Biochimie 89:1464-73
Heider, T Ryan; Lyman, Suzanne; Schoonhoven, Robert et al. (2007) Ski promotes tumor growth through abrogation of transforming growth factor-beta signaling in pancreatic cancer. Ann Surg 246:61-8
Black, Dalliah; Bird, Mark A; Hayden, Melissa et al. (2004) TNF alpha-induced hepatocyte apoptosis is associated with alterations of the cell cycle and decreased stem loop binding protein. Surgery 135:619-28
Black, Dalliah; Lyman, Suzanne; Heider, T Ryan et al. (2004) Molecular and cellular features of hepatic regeneration. J Surg Res 117:306-15
Black, Dalliah; Bird, Mark A; Samson, Charles M et al. (2004) Primary cirrhotic hepatocytes resist TGFbeta-induced apoptosis through a ROS-dependent mechanism. J Hepatol 40:942-51
Bird, Mark A; Lange, Patty A; Schrum, Laura W et al. (2002) Cholestasis induces murine hepatocyte apoptosis and DNA synthesis with preservation of the immediate-early gene response. Surgery 131:556-63
Black, Dalliah M; Behrns, Kevin E (2002) A scientist revisits the atrophy-hypertrophy complex: hepatic apoptosis and regeneration. Surg Oncol Clin N Am 11:849-64