There are presently about 39,000 new cases of renal cancer in the United States each year, resulting in over 13,000 deaths. Traditional radiation and chemo-therapies are ineffective. Early detection is also difficult because of a lack of early symptoms. 40-50% of patients develop metastatic disease, for whom the 5-year survival rate is only ~10%. Such grim statistics point to an urgent need for better understanding of the kidney cancer biology. One important characteristic of kidney cancer is its strong association with lesions in one gene, the von Hippel-Lindau (VHL) tumor suppressor gene. The gene is named after the familial VHL disease. Up to 70% of the carriers of germ line VHL mutations develop renal cell carcinoma of the clear-cell type (ccRCC). In addition, loss of VHL function, including somatic mutations and epigenetic defects, is found in 70-90% of sporadic ccRCC. The best-documented function of VHL is its E3 ubiquitin ligase activity that targets the alpha subunit of the hypoxia-inducible factor (HIF-a). However, VHL also possess multiple HIF-independent functions. It is not known how loss of the complex spectrum of VHL functions collectively contribute to the initiation of ccRCC. The uncertainties are further compounded by a lack of VHL cancer model in mouse. Our studies in the past funding period have elucidated a novel epithelial-to-mesenchymal transition (EMT) pathway that has been implicated in kidney injury and fibrosis. Most importantly, using a new conditional knockout strategy, we have, for the first time, developed a genuine mouse ccRCC model that recapitulates features of kidney inflammation and fibrosis, leading to metastatic ccRCC. This model should allow us to elucidate the earliest event in ccRCC and point to potential preventive and curative strategies for this deadly disease. Four Specific Aims are proposed to characterize the new VHL cancer model: Aim 1. To determine the tissue origin and the role of VHL-HIF axis in VHL knockout lesions. Aim 2. To elucidate the molecular and cellular mechanisms of EMT signaling in VHL mutant cells. Aim 3. To elucidate the mechanism of inflammation in VHL mutant kidney. Aim 4. To profile the gene expression pattern associated with VHL tumor progression.