Beta-Catenin and Prostate Development

描述（由申请人提供）： 作为一名独立研究人员，我的目标是使用双管齐下的方法来研究前列腺疾病：（1）我将使用发育中的前列腺作为模型系统，以阐明以前未被认识到的有助于前列腺生长的信号通路，（2）我将在良性前列腺增生或前列腺癌的临床相关模型中研究这些信号通路。我的研究重点是在这个建议是测试的总体假设，β-连环蛋白是需要在胚胎小鼠前列腺原基，尿生殖窦（UGS）的前列腺导管发育。前两个具体目标将调查β-连环蛋白在前列腺出芽过程中的功能。他们将检验以下假设：（1）雄激素刺激UGS中β-连环蛋白介导的转录， β-连环蛋白是出芽所必需的，和（2）β-连环蛋白在前列腺芽形成期间介导细胞粘附，并且β-连环蛋白的这种作用是出芽所必需的。最后一个目的是研究β-连环蛋白在出芽过程中的调控。它将检验假设：（3）成纤维细胞生长因子10是在前列腺出芽过程中稳定β-连环蛋白所必需的。这项研究计划很有可能导致β-连环蛋白作为前列腺出芽的核心参与者的鉴定。我的计划是使用上述结果作为初步数据，在该奖项的第3年申请RO 1或R 03资助，重点是良性前列腺增生或前列腺癌的机制。作为K 01获奖者，我将遵循职业发展计划，每个获奖年度都有非常具体的研发里程碑。我将定期与我的导师和咨询委员会会面，并完成癌症生物学的教学课程。我将获得经验培训，在赠款写作，Wnt/β-连环蛋白信号，良性前列腺增生，前列腺癌。这项计划将扩展我的研究专长，并加强我在前列腺疾病研究方面的培训。威斯康星州大学是NIDDK赞助的奥布莱恩泌尿学研究中心，是NCI赞助的综合癌症中心，拥有近40个前列腺研究实验室，为我作为未来的前列腺科学家提供了理想的培训环境。 在前列腺发育期间调节生长的生物因素也被认为是前列腺疾病期间不适当生长的原因。拟议的研究将调查如何 β-连环蛋白与男性性激素相互作用以控制前列腺发育，因为这些相互作用可能为前列腺疾病期间如何激活不适当的前列腺生长提供线索。

DESCRIPTION (provided by applicant): My goal as an independent researcher is to use a two-pronged approach to study prostate disease: (1) I will use the developing prostate as a model system for elucidating previously unrecognized signaling pathways that contribute to prostate growth and (2) I will investigate these signaling pathways in clinically relevant models of benign prostate hyperplasia or prostate cancer. My research focus in this proposal is to test the overarching hypothesis that beta-catenin is required for prostate ductal development in the embryonic mouse prostate anlagen, the urogenital sinus (UGS). The first two specific aims will investigate the function of beta-catenin during prostatic budding. They will test hypotheses that (1) androgens stimulate beta-catenin-mediated transcription in the UGS and that beta-catenin is required for budding, and (2) beta-catenin mediates cell adhesion during prostatic bud formation and that this action of beta-catenin is required for budding. The last aim investigates the regulation of beta-catenin during budding. It will test the hypothesis that (3) fibroblast growth factor 10 is required for stabilizing beta-catenin during prostatic budding. This research plan has a high probability of leading to the identification of beta-catenin as a central player in prostatic budding. My plan is to use the above results as preliminary data to apply, in year 3 of this award, for an RO1 or R03 grant focused on mechanisms of benign prostate hyperplasia or prostate cancer. As a K01 recipient, I will follow a career development plan with very specific research and development milestones for each award year. I will meet regularly with my mentors and advisory committee and complete didactic coursework in cancer biology. I will obtain experiential training in grant writing, Wnt/ beta-catenin signaling, benign prostate hyperplasia, and prostate cancer. This plan will stretch my research expertise and enhance my training in prostate disease research. The University of Wisconsin is an NIDDK-sponsored O'Brien Urology Research Center, an NCI-sponsored Comprehensive Cancer Center, and boasts nearly 40 prostate research labs, culminating in an ideal training environment for me as a future prostate scientist. Biological factors regulating growth during prostate development are also believed to be responsible for inappropriate growth during prostate disease. The proposed research will investigate how the beta-catenin protein interacts with male sex hormones to control prostate development, as these interactions might provide clues for how inappropriate prostate growth is activated during prostate disease.