Reza Zarnegar, Ph.D.
|1996-2000 Associate Professor (with tenure),
Department of Pathology, University of Pittsburgh
1991-1995 Assistant Professor, Department of Pathology, University of Pittsburgh
1989-1991 Research Assistant Professor, Department of Pathology, Duke University Medical Center
1987 Ph.D. in Biochemistry, East Tennessee State University
1983 M.S. in Microbiology, East Tennessee State University
1978 B.S. in Biology, University of Razi, Iran
Keynote Address Abstract
Novel Aspects of HGF/HGFR Axis in Tissue Homeostasis and Disease
Dr. Zarnegar is a Tenured Professor of Pathology and a member of the Division of Experimental Pathology. His laboratory is focused on determining the physiological and pathological role of the HGF/Met axis in normal tissue homeostasis and disease processes. Dr. Zarnegar discovered Hepatocyte Growth Factor (HGF) in the 1980’s and since then, has devoted his research efforts to understanding this important signaling factor. HGF and its cell surface tyrosine kinase receptor (Met) play an important role in tissue homeostasis, and the deregulation of HGF/Met axis has pathological consequences such as cancer. An in-depth understanding of the molecular mechanisms of HGF/Met function will not only shed light on normal tissue physiology but also on understanding the basis of its pathogenic effects and thus may provide opportunities for rational drug design to combat various diseases ranging from tissue degeneration to cancer.
Through structural and functional studies, Dr. Zarnegar’s laboratory has discovered novel mechanisms by which the Met receptor regulates hepatocyte growth and liver homeostasis. Specifically, his lab found that, in normal liver, the extracellular domain (a.k.a. the ectodomain) of Met directly binds to Fas (a death promoting receptor) and acts as a natural antagonist of FasL thereby prohibiting Fas aggregation and cell killing. They have determined that Fas sequestration by Met is abrogated in human fatty liver disease hence making these livers vulnerable to cell death and development of NASH. T he mechanism through which liver cells die is mainly via activation of the Fas axis. Unregulated hepatocyte death occurs in a variety of hepatic diseases including hepatitis caused by chemical, viral or metabolic etiologies which may ultimately culminate in end-stage liver disease including liver cancer and hepatic failure requiring liver transplantation. Dr. Zarnegar’s group has mapped the interaction region in Met and Fas to a 12 amino acid region containing a core YLGA motif in Met and show that Met and its synthetic peptide derivatives prohibit FasL binding to Fas, Fas activation and hepatocyte death in vitro and in animal models of NASH. His lab is currently expanding these structure-function studies of Met and he will present his recent findings in this area.
In a separate project, Dr. Zarnegar’s lab has discovered that, in human breast cancer, the HGF gene promoter is prone to deletion mutagenesis in a DNA element located 750 bp upstream from the transcription start site. This novel HGF promoter element consists of a mononucleotide repeat of 30As and is referred to as DATE (Deoxy Adenosine Tract Element). Mutation of DATE results in reactivation/lack of proper silencing of HGF gene expression in carcinoma tissues. Normally, the HGF gene is transcriptionally silenced in differentiated breast epithelial cells. Through functional studies, they showed that DATE mutation (shortening) has profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions leading to constitutive activation of the HGF gene promoter in human breast carcinoma cells lines. Interestingly, they found that 51% (19/37) of African Americans and 15% (8/53) of Caucasians with breast cancer harbor the truncated DATE variant (25As or less) in their breast tumors and that the truncated allele significantly associates with cancer incidence and aberrant HGF expression. Dr. Zarnegar will also present these results in his seminar to the ETSU Department of Biochemistry on April 10, 2009.
Relevant Recent Publications: