Chemical Genetics Analysis Targeted to the Mouse Prostate Epithelium

描述（由申请人提供）：本研究项目的总体目标是开发一种可用于选择性破坏小鼠前列腺上皮蛋白激酶的通用方法。这对于理解蛋白激酶在前列腺上皮正常发育和恶性肿瘤进展中的作用至关重要。如果要将蛋白激酶用作开发用于治疗前列腺上皮疾病（包括癌症）的小分子药物的靶标，这种理解是必不可少的。开发一种成功的破坏小鼠前列腺蛋白激酶的策略需要满足两个单独的目标。首先，必须选择性地破坏前列腺上皮中的蛋白激酶。其次，这种破坏必须暂时调节，因为蛋白激酶功能丧失的确切时间对于理解蛋白激酶在前列腺发育和成熟前列腺功能中的作用非常重要。同样，对蛋白激酶破坏的时间控制将需要研究肿瘤的发生和进展。我们建议研究的模型系统涉及应激激活MAP激酶的c-Jun nh2末端激酶（JTSIK）组。预计该JNK特异性模型的开发将为指导将相同方法应用于其他蛋白激酶提供信息。建立一种选择性破坏小鼠前列腺上皮JNK的方法。2. 开发一种可用于选择性和暂时性调节JNK在小鼠前列腺上皮中的功能的通用方法。

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.