Role of mTORC1 In The Regulation Of Prostatic Branching Morphogenesis

描述（由申请人提供）：前列腺形态发生是由一系列复杂的信号事件级联调控的，这些信号事件随时间和空间精确整合。几十年的研究已经清楚地表明，泌尿生殖窦间质和上皮之间的细胞间通讯对前列腺发育的开始至关重要。现在，主要的挑战是阐明细胞内的信号转导网络，这些信号转导网络整合了组织间室之间的旁分泌串扰。在本应用中，我们建议通过研究mTOR（哺乳动物雷帕霉素靶点）信号复合物如何在整合上游信号以促进或抑制前列腺生长、发育和分化中发挥关键作用来解决这一重要问题。在使用药理学和遗传扰动相结合的已发表和初步数据中，我们表明内源性mTORC1活性实际上抑制前列腺分支。在这里，我们提出测试mTORC1的这种抑制作用是否可能源于对前列腺分支所需的上游雄激素和成纤维细胞生长因子信号的负反馈。然后，我们将研究mTORC1信号下游的细胞机制可能解释其对前列腺器官发生的影响。利用我们实验室之前生成的新型转基因小鼠模型的组合，诱导mTORC1的功能增加或丧失，再加上长期延时成像技术，我们已经完全准备好扩展我们在前列腺形态发生中的PI3K（磷酸肌醇-3激酶）信号传导的工作，该工作由之前的NIDDK K08奖申请资助。这项工作具有特别的相关性，因为成人前列腺异常生长的条件，如良性前列腺增生，无疑是由许多在胚胎前列腺发育过程中活跃的信号网络调节的。如果我们能够理解和操纵这些相同的途径，我们可能会发现新的治疗范例，以解决这一重要的公共卫生问题。

DESCRIPTION (provided by applicant): Prostatic morphogenesis is regulated by a complex cascade of signaling events, precisely integrated over time and space. Decades of research have clearly demonstrated that intercellular communication between urogenital sinus mesenchyme and epithelium is critical for the initiation of prostatic development. Now, the major challenge is to elucidate the intracellular signal transduction networks that integrate this paracrine crosstalk between tissue compartments. In this application, we propose to address this important problem by studying how the mTOR (mammalian target of rapamycin) signaling complex may serve a critical role in integrating upstream signals to promote or inhibit prostatic growth, development and differentiation. In published and preliminary data using a combination of pharmacologic and genetic perturbations, we show that endogenous mTORC1 activity actually suppresses prostatic branching. Here, we propose to test whether this inhibitory role of mTORC1 may stem from negative feedback to upstream androgen and fibroblast growth factor signals required for prostatic branching. Then, we will investigate what cellular mechanisms downstream of mTORC1 signaling may account for its effects on prostatic organogenesis. Using a combination of novel transgenic mouse models that have been previously generated in our lab to induce mTORC1 gain- or loss-of-function, paired with long-term time lapse imaging techniques, we are perfectly poised to extend our work on PI3K (phosphoinositide-3-kinase) signaling in prostatic morphogenesis funded by a previous NIDDK K08 award application. This work is of particular relevance because conditions of abnormal prostatic growth in the adult, such as benign prostatic hyperplasia, are undoubtedly regulated by many of the same signaling networks active during embryonic prostate development. If we can understand and manipulate these same pathways, we may discover new treatment paradigms for this important problem of public health. PUBLIC HEALTH RELEVANCE: There is increasing evidence that many of the signaling pathways that regulate prostatic growth during embryonic development are reactivated in adult diseases, such as benign prostatic hyperplasia and cancer. We have preliminary data that suggests the mTORC1 signaling pathway is important during prostatic development, and we propose to study how its activation may suppress the growth of prostatic epithelial tubules. This pathway is of particular interest because there are numerous drugs available for modulating its activity that may be useful for the treatment of human prostate diseases once we fully understand how the pathway works.