Chemical Genetics Analysis Targeted to the Mouse Prostate Epithelium

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DESCRIPTION (provided by applicant): The overall goal of this research program is to develop a general method that can be used to disrupt protein kinases selectively in the mouse prostate epithelium. This will be critical for understanding the role of protein kinases in the normal development of the prostate epithelium and also during malignant tumor progression. This understanding is essential if protein kinases are to be used as targets for the development of small molecule drugs for the treatment of diseases of the prostate epithelium, including cancer. The development of a successful strategy for disrupting protein kinases in the mouse prostate requires that two separate goals are met. First, the protein kinase must be selectively disrupted in the prostate epithelium. Second, the disruption must be temporally regulated since the exact timing of protein kinase loss- of-function will be very important for understanding the role of the protein kinase in both the development of the prostate and the function of the mature prostate gland. Similarly, temporal control of protein kinase disruption will be required for studies of tumor initiation and progression. The model system that we propose to examine involves the c-Jun NH2-terminal kinase (JTSIK) group of stress-activated MAP kinases. It is anticipated that the development of this specific model for JNK will provide information that will guide the application of the same method to other protein kinases The Specific Aims of this proposal are to examine: 1. Develop a method to selectively disrupt JNK in the murine prostate epithelium.. 2. Develop a general method that can be used to selectively and temporally regulate the function of JNK in the murine prostate epithelium.