Somatic mutation of the von Hippel-Lindau (VHL) tumor suppressor gene is associated with sporadic renal cell carcinoma (RCC), and germline VHL mutation results in VHL disease with predisposition to RCC and/or other neoplasms. Despite striking genotype-phenotype correlations in VHL disease, disruption of specific pVHL functions is not directly related to the spectrum of clinical disease. I will examine representative RCC- predisposing VHL mutations in vitro and in vivo to identify mutant pVHL functions important for renal tumorigenesis. I hypothesize that VHL mutations exert their tissue-specific effects by disrupting wild-type or introducing novel pVHL functions and that other genetic events are necessary to cause invasive kidney cancer. I will delineate the key genetic events using chemical and insertional mutagenesis. Potassium bromate, a byproduct of water distillation, causes oxidative damage, mutations, and RCC in the renal tubules of rats. I will use this biologically-relevant, kidney-targeted environmental toxin to perform chemical mutagenesis in wild-type and VHL-mutant mice. I will supplement this approach with insertional mutagenesis using a mammalian transposition system targeted to the renal parenchyma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30ES015248-05
Application #
7900013
Study Section
Special Emphasis Panel (ZRG1-F09-S (20))
Program Officer
Humble, Michael C
Project Start
2006-08-01
Project End
2011-05-31
Budget Start
2010-08-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$25,519
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hacker, Kathryn E; Lee, Caroline Martz; Rathmell, W Kimryn (2008) VHL type 2B mutations retain VBC complex form and function. PLoS One 3:e3801