): Clear-cell renal carcinoma (RCC), the most common cancer of the kidney, occurs in 27,000 individuals in the US each year and is responsible for 11,000 deaths annually. The treatment of RCC remains frustrating to the oncologist and locally unrespectable and metastatic disease has dismal prognosis. The von Hippel-Lindau (VHL) tumor suppressor gene has been implicated in the pathogenesis of hereditary and in the majority of sporadic RCCs (more than 75 percent). The applicants have preliminary data that transforming growth factor-beta 1 (TGF-B1) is a novel target for the VHL gene product (pVHL) and that pVHL decreases TGF-B1 mRNA half-life. Studies have also shown that neutralizing anti-TGF-B1 antibodies inhibits subcutaneous VHL-associated RCC tumors in nude mice. The first half of the proposal aims to dissect the molecular mechanisms by which pVHL regulates TGF-B1. They will first aim to delineate cis-sequences in the TGF-B1 mRNA responsive to pVHL and then characterize proteins binding to the cis-elements. The second half of the proposal will be focused on defining the biological significance of elevated TGF-B1 in RCCs. The applicants will first define the loss of responsiveness of RCC lines in vitro to exogenous TGF-B1. Then, they will aim to understand the mechanism of RCC tumor inhibition by anti-TGF-B1 antibodies and define the role of TGF-B1 in metastasis. These focused studies form the beginnings of a framework to understand the pathogenesis of VHL-associated RCCs and to identify novel avenues for the treatment of RCC. The work described will be performed in the outstanding environment of Harvard Medical School and in the laboratory of Vikas P. Sukhatme, M.D., Ph.D., an experienced researcher in the field of cancer biology (WT-1, Egr-1). New methodologies the applicant will learn include RNA gel shifts, RNase protection assays, UV crosslinking, mutagenesis, mutation analysis, animal work and immunohistochemistry.
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