The long term objective of these studies is to develop, characterize, and refine novel strategies to manipulate prostate specific gene expression in order to facilitate the establishment of transgenic mouse models and gene therapies for translational prostate cancer research. The rationale for these studies is that direct genetic manipulation of the prostate translates into transgenic models that hereditarily exhibit reproducible pathologies characteristic of human disease. These can be used simultaneously by investigators around the world to study the molecular basis of initiation, transformation and progress of prostate cancer. As well, these studies translate into the design of prostate-specific gene- based therapies that can be tested rapidly in tahe animal models. To this end, the principal investigator and his collaborators will continue development of a novel system based on the regulatory elements of the rat probasin (PB) gene shown during the term of the initial SPORE award to target developmentally and hormonally regulated heterologous gene expression, specifically to the prostate in transgenic mice. Lines of transgenic mice have already been established carrying either a PB-ras construct that reproducibly develop prostate hyperplasia or a PB-Tag construct that reproducibly develop prostate cancer. Having demonstrated that the murine prostate can be transformed as a consequence of targeted oncogene expression, it will be a primary objective of this project to thoroughly characterize the initiation, development and progression of prostate disease in these mice at the histologic, pathologic and molecular levels and establish PB-myc mice to compliment these models. Since the role of p53 in the development of prostate cancer metastases has been demonstrated using p53-deficient mice, a prostate-specific gene knock-out system based on the cre-lox recombinase strategy will be developed to facilitate further characterization of the loss of wild-type tumor suppressor genes and other genes identified through genetics studies to correlate with prostatic disease. This approach will also facilitate investigation into the role of the retinoblastoma (Rb) protein in the progression of prostate cancer since Rb-deficient mice are not sufficiently viable for these studies. In order to further facilitate translational research, the prostate-specific expression system will be used to generate a novel prostate-specific p53-based gene therapy strategy designed to exploit the p53-dependent apoptotic pathway for the treatment of prostate cancer. The efficacy of this strategy will be tested in the transgenic models. Therefore, the strategies designed to manipulate prostate-specific gene expression developed in this project will be used both to identify biological factors involved in the progression of prostate cancer and in the development and testing of innovative medical strategies for the prevention and treatment of prostate cancer.
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