Regulation of Postnatal Epididymal Cell Proliferation

产后附睾细胞增殖的调节

基本信息

批准号：
8811855
负责人：
Barry T. Hinton
金额：
$ 31.16万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811855
关键词：
Adult Androgens Apoptosis Area Cell Proliferation Cell Proliferation Regulation Cell Survival Cells Congenital Abnormality Cytoprotection Data Defect Development Duct (organ) structure Electroporation Ensure Epididymis Epithelium Event Fetal Development Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gene-Modified Growth Growth Factor Growth and Development function Human Imaging Techniques Lead Ligands Liquid substance MAP Kinase Gene Male Infertility Malignant Neoplasms Microinjections Mus Nature Organ Outcome Outcome Study PTEN gene Pathway interactions Phosphoric Monoester Hydrolases Play Process Protein Kinase Publishing Regulation Reproductive Biology Role Signal Pathway Signal Transduction Signal Transduction Pathway Sperm Maturation Staging Testing Time Tube Up-Regulation Work apical membrane base human FRAP1 protein in vivo interest novel postnatal receptor research study

项目摘要

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.

描述（申请人提供）：附睾，特别是起始段，在精子的成熟过程中发挥着重要作用，如果起始段没有完全发育，就会导致男性不育。该提案的中心假设是附睾功能缺陷是由异常的初始节段发育引起的，考虑到人类附睾具有初始节段状上皮，了解该区域的发育非常重要。我们对了解调节这一重要器官发育的机制特别感兴趣，因为异常发育也可能导致附睾功能的破坏。因此，在该应用中，非常重视了解发育过程中细胞增殖的调节。尽管雄激素调节附睾发育，但推测睾丸腔液因子（lumicrine Factor）发挥着主要作用。这是一个新颖的假设，因为发光因子仅与保护初始片段免于凋亡有关。此外，该申请中概述的实验将挑战这样的教条：细胞增殖在出生后没有受到差异性调节。我们的工作假设是，随着发光因子从调节出生后的细胞增殖转变为调节成年后的细胞存活，细胞从增殖状态转变为非增殖状态。这是通过上游发光生长因子配体与初始节段细胞顶膜上的同源受体相互作用来调节特定信号传导途径来实现的，从而确保形成完全发育且功能正常的初始节段。为了检验这一假设，提出了三个具体目标：（1）检验管腔因子在出生后一段时间内调节初始节段细胞增殖的假设，（2）检验管腔 FGF 和下游信号通路的假设调节出生后起始段细胞增殖信号转导通路的表达，（3）检验细胞增殖所需的FGF/FGFR/PI3K/Akt/mTOR通路之间的转换的假设，细胞保护所需的toFGF/FGFR/pERK/pMEK途径是出生后发育初始阶段特定阶段PTEN上调、激活和/或重新分布的结果。这项研究的预期结果不仅会对人们知之甚少的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，他们将让我们了解附睾特定区域的发育在临床上的重要性，以及发育过程中附睾生长的调节如何有助于我们理解为什么附睾很少死于癌症。