Chemical Genetics Analysis Targeted to the Mouse Prostate Epithelium

描述(由申请人提供)：该研究计划的总体目标是开发一种通用方法，可用于选择性地干扰小鼠前列腺上皮中的蛋白激酶。这对于理解蛋白激酶在前列腺上皮的正常发育和恶性肿瘤进展过程中的作用至关重要。如果要将蛋白激酶作为小分子药物的靶点，用于治疗包括癌症在内的前列腺上皮疾病，这种理解是必不可少的。要开发一种成功的策略来破坏小鼠前列腺中的蛋白激酶，需要达到两个不同的目标。首先，必须有选择地破坏前列腺上皮中的蛋白激酶。其次，这种干扰必须在时间上进行调节，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癌功能中的作用非常重要。同样，在研究肿瘤的发生和发展时，也需要对蛋白激酶的破坏进行时间控制。我们建议研究的模型系统涉及c-jun氨基末端激酶(JTSIK)组的应激激活的MAP激酶。JNK的这一特定模型的发展预计将提供指导同样方法应用于其他蛋白激酶的信息。本提案的具体目的是检查：1.开发一种选择性地干扰小鼠前列腺上皮中JNK的方法。2.建立一种通用的方法，可用于选择性和时间性地调节JNK在小鼠前列腺上皮细胞中的功能。

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.