Regulation of Postnatal Epididymal Cell Proliferation

描述（由申请方提供）：附睾，特别是起始段，在精子成熟中起重要作用，如果没有完全发育的起始段，将导致男性不育。该建议的中心假设是，附睾功能的缺陷是由异常的起始段发育引起的，考虑到人类附睾具有起始段样上皮，了解该区域的发育是很重要的。我们特别感兴趣的是了解调节这一重要器官发育的机制，因为发育异常也可能导致附睾功能紊乱。因此，在本申请中，重视理解发育期间细胞增殖的调节。虽然雄激素调节附睾发育，但推测光分泌因子（睾丸腔液因子）起主要作用。这是一个新的假说，因为光泌素因子仅与保护起始节段免于发生凋亡有关。此外，在申请中概述的实验将挑战教条， 细胞增殖在出生后没有差异调节。我们的工作假设是，当光泌因子从出生后调节细胞增殖转变为成年后调节细胞存活时，细胞从增殖状态转变为非增殖状态。这是通过上游光泌素生长因子配体与初始节细胞顶膜上的同源受体相互作用调节特异性信号传导途径来实现的，从而确保形成完全发育和正常功能的初始节。为了检验这一假设，提出了三个具体目标：（1）为了检验光泌素因子在出生后期间的时间窗内调节初始节段细胞增殖的假设，（2）为了检验腔FGF和下游信号传导途径调节出生后初始节段中细胞增殖信号传导途径的表达的假设，（3）验证细胞增殖所需的FGF/FGFR/PI 3 K/Akt/mTOR通路与细胞保护所需的FGF/FGFR/pERK/pMEK通路之间的转换是在出生后发育的初始段的特定阶段PTEN上调、激活和/或重新分布的结果的假设。这项研究的预期结果不仅将对生殖生物学领域产生重大影响，而且还将有助于我们了解导管/管伸长的基本过程。具体来说，他们将提供一个附睾特定区域的发展是如何重要的临床和如何在发展过程中的附睾生长的调节将有助于我们理解为什么附睾很少屈服于癌症的理解。

DESCRIPTION (provided by applicant): The epididymis, and in particular, the initial segment, play an important role in the maturation of spermatozoa and without a fully developed initial segment, male infertility will result. The central hypothesis of this proposal is that defects in epididymal function arise from abnormal initial segment development and considering that the human epididymis has an initial segment-like epithelium, it is important to understand the development of this region. We are especially interested in understanding the mechanisms that regulate the development of this important organ because disruptions to epididymal function may also arise as a consequence of abnormal development. Therefore, in this application a premium is placed upon understanding the regulation of cell proliferation during development. Although androgens regulate epididymal development, lumicrine factors (testicular luminal fluid factors) are hypothesized to play a major role. This is a novel hypothesis because lumicrine factors have only been associated with protection of the initial segment from undergoing apoptosis. Further, the experiments outlined in the application will challenge the dogma that cell proliferation is not differentially regulated postnatally. Our working hypothesis is that as lumicrine factors switch from regulating cell proliferation postnatally to regulating cell survival in adulthood, cells move from a proliferative state to a non-proliferative state. This is achieved by regulating specific signaling pathways via upstream lumicrine growth factor ligand(s) interacting with their cognate receptors on the apical membrane of initial segment cells, thereby ensuring the formation of a fully developed and proper functioning initial segment. To test this hypothesis, three specific aims are proposed: (1) To test the hypothesis that lumicrine factors regulate initial segment cell proliferation in a window of time during the postnatal period, (2) To test the hypothesis that luminal FGFs and downstream signaling pathways regulate the expression of cell proliferation signal transduction pathways in the postnatal initial segment, (3) To test the hypothesis that the switch between the FGF/FGFR/ PI3K/Akt/mTOR pathway, which is required for cell proliferation, toFGF/FGFR/pERK/pMEK pathway, which is required for cell protection is the result of PTEN upregulation, activation and/or redistribution at a specific stage during initial segment postnatal development. The anticipated outcomes of this study will not only have a major impact on an area of reproductive biology that has been poorly understood, but will also contribute to our understanding of the fundamental process of duct/tube elongation. Specifically they will provide an understanding of how the development of one epididymal specific region is important clinically and how the regulation of growth of the epididymis during development will contribute to our understanding of why the epididymis rarely succumbs to cancer.