Regulation of Postnatal Epididymal Cell Proliferation

描述(申请人提供)：附睾部，特别是起始段，在精子成熟过程中起着重要作用，如果没有充分发育的起始段，将导致男性不育。这一建议的中心假设是，附睾功能的缺陷是由起始节段发育异常引起的，考虑到人类附睾具有起始节段样上皮，了解该区域的发育是很重要的。我们对了解调节这个重要器官发育的机制特别感兴趣，因为附睾功能的中断也可能是发育异常的结果。因此，在这一应用中，理解发育过程中细胞增殖的调节是非常重要的。虽然雄激素调节附睾发育，但光分泌因子(睾丸腔液因子)被假设为起主要作用。这是一个新的假说，因为光分泌因子只与保护起始片段免受细胞凋亡有关。此外，应用程序中概述的实验将挑战以下教条 细胞增殖在出生后不受差异调控。我们的工作假设是，随着光分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，细胞从增殖状态转移到非增殖状态。这是通过上游的鲁米克林生长因子配体(S)与其在起始片段细胞顶膜上的同源受体相互作用来调节特定的信号通路，从而确保形成一个发育充分和功能正常的起始片段。为了验证这一假说，提出了三个特定的目标：(1)检验光分泌因子在出生后一段时间内调节起始段细胞增殖的假说；(2)检验管腔FGFs及其下游信号通路调节出生后起始段细胞增殖信号转导通路表达的假说；(3)检验细胞增殖所需的FGF/FGFR/PI3K/Akt/mTOR通路之间的切换是PTEN上调的结果的假说。在出生后发育的最初阶段的特定阶段的激活和/或再分配。这项研究的预期结果不仅将对生殖生物学这个一直知之甚少的领域产生重大影响，而且还将有助于我们理解管/管延长的基本过程。具体地说，它们将使我们了解一个附睾特定区域的发育在临床上是如何重要的，以及在发育过程中对附睾体生长的调节将如何有助于我们理解为什么附睾很少屈服于癌症。

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.