1997 Research Grant Awards

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. Zbar's team at the National Cancer Institute) and by Dr. Othon Iliopoulos of Boston (a member of Dr. William Kaelin's team) have been favorably reviewed by the Research Advisory Board. Myriam Gorospe, chairman of the Research Committee, has provided the attached summary.

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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 process of angiogenesis in general. He will first examine whether binding of VHL to elongins 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 VHL regulates VEGF expression; since it has been shown that it involves primarily alterations in VEGF mRNA stability, he proposes to directly examine the factors that regulate VEGF mRNA stability and explore their potential regulation by pVHL. Finally, he would like to identify other genes whose expression is regulated by VHL.

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), 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 formation of pVHL/elongin complexes) 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 assays: 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.

Myriam Gorospe, Ph.D., Chair, Research Committee

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