We are very pleased to announce that the two research proposals submitted by Drs. James Gnarra of Louisiana State University, formerly a member of Dr. Linehan's team at the National Cancer Institute (NCI) and by Dr. Othon Iliopoulos of Boston, a member of Dr. William Kaelin's team, have been favorably reviewed by the Research Advisory Board. Dr. Gnarra's proposal is aimed at understanding the cellular function of the von Hippel-Lindau protein (pVHL). Specifically, he plans to investigate how VHL regulates the expression of vascular endothelial growth factor (VEGF) and the basic process of angiogenesis, or the building of new blood vessels. He will first examine whether binding of VHL to substances known as "elongins" (A, B, and C) is necessary for VHL function (for example its function as a regulator of VEGF expression, etc) by making and studying mutant forms of VHL that do not bind to elongins.Second, he plans on focusing directly on how pVHL controls VEGF expression, a very complicated process involving many biological steps. He will examine which step or steps are regulated by pVHL.

Dr. Iliopoulos proposes to investigate the mechanisms whereby VHL exerts its tumor suppressive activity. Since the domain that binds to elongins is often mutated in renal cell carcinoma (RCC) in the general population, he postulates that interaction with elongins may be important for tumor suppression. Therefore, he plans to determine whether or not binding to elongins is necessary and/or sufficient to suppress tumor formation. In the first aim, he addresses whether inhibition of elongin activity (through the interaction of pVHL with elongin) is necessary for tumor suppression. He plans to generate pVHL mutants with impaired ability to bind to elongins and assess the function of these mutants in two trials: tumor formation in nude mice and inhibition of VEGF expression. His second aim is to determine whether inhibition of elongin activity (through pVHL/elongin interaction) is sufficient for tumor suppression. He will study directly if blocking elongin activity is enough to suppress growth, by generating mutant forms of elongins and testing them in VHL-deficient cells. He will employ the same two assays (tumor formation in nude mice and VEGF expression) to address this question.

Dr. Iliopoulos received his M.D. in 1985 from Athens Kapodistan University in Athens, Greece. He held a research fellowship at Johns Hopkins Hospital from 1983 until 1989, working in the area of allergy-immunology. He began his medical residency at the University of Wisconsin Hospitals in 1989, where he was chief resident in medicine during 1991 and 1992. He joined the Dana-Farber Institute in 1992. He has been studying VHL since 1993. He was a speaker at the VHL Family Alliance conference in Bethesda in May 1997. (Award $20,000)

Dr. Gnarra received his Ph.D. in 1987 from the University of Virginia. He held a research fellowship at the NIH under Dr. Richard Klausner from 1987 to 1991. He then joined Dr. W. Marston Linehan's group at the NCI and was a member of the team headed by Drs. Berton Zbarm, Michael Lerman, and Linehan that found the VHL gene. He then went on to show the role of the VHL gene in non-hereditary renal cancers. Dr. Gnarra accepted a position as Associate Professor of Biochemistry and Molecular Biology at the Luisiana State University Medical Center in New Orleans in 1996. He holds a joint appointment in the Department of Biometry and Genetics and is a member of the Stanley S. Scott Center and the Program in Human Molecular Genetics at the LSU Medical Center. (Award $20,000)

As published in the 1997 Research Report