(Taken directly from the application) The long term goal of Project 4 is to understand the molecular basis of bladder tumorigenesis by testing the hypothesis that there are two pathways that can produce a bladder tumor. The first, where p16 is involved, frequently produces superficial papillary tumors with a tendency to recur, but unlikely to progress. The second, which involves p53, starts as a carcinoma in situ and frequently progresses. Towards this goal, we will develop model systems of tumorigenesis in transgenic mice, which contain oncogenetic alterations frequently observed in human transitional cell carcinoma. The need for such tailored system comes from the fact that, although bladder tumors have been experimentally produced by chemical agents, the molecular mechanisms triggering such tumors are frequently unknown, and in the cases where they have been analyzed, they rarely mimic the oncogenic events seen in human transitional cell carcinomas, i.e., changes in epidermal growth factor receptor (EGFR), H-ras, p16 and p53. Until recently, it had been impossible to direct the expression of a gene specifically to the urothelium. However, the recent isolation of such a urothelial specific promoter, from the uroplakin II (UPII) gene, will enable us to generate transgenic mouse lines with specific oncogenic changes in the urothelium. We will therefore use the UPII promoter to drive the urothelial expression of normal and activated EGFR, activated H-ras, and a dominant negative mutant of p53. We will also utilize the cre/loxP system to specifically inactivate p53 and p16 in the mouse urothelium. The effects of these transgenes on urothelial growth and tumor formation will be examined. To maximize the tumor yield, the genes will also be used in specific combinations and, if necessary, together with subcarcinogenic doses of bladder carcinogens. To assess the crucial role of these alterations in the bladder tumors, we will analyze if the appropriate pathways are activated. These model systems of tumorigenesis and the test of the two pathway hypothesis of bladder cancer pathogenesis should lead to a better understanding of the pathogenesis of bladder tumors, and it may also contribute to a more informed therapy of human transitional cell carcinoma.
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