Regulation of Postnatal Epididymal Cell Proliferation

描述（由申请人提供）：附睾，特别是初始段，在精子成熟过程中起着重要作用，如果没有完全发育的初始段，将导致男性不育。本研究的中心假设是附睾功能缺陷是由初始节段发育异常引起的，考虑到人类附睾具有初始节段样上皮，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，因为附睾功能的破坏也可能是异常发育的结果。因此，在这一应用中，理解发育过程中细胞增殖的调控是非常重要的。虽然雄激素调节附睾的发育，但据推测管腔因子（睾丸管腔液因子）起主要作用。这是一个新颖的假设，因为发光因子仅与保护初始段免受细胞凋亡有关。此外，应用程序中概述的实验将挑战

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.