Regulation of Postnatal Epididymal Cell Proliferation

产后附睾细胞增殖的调节

• 批准号: 8236636
• 负责人: Barry T. Hinton
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236636
• 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; 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

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. PUBLIC HEALTH RELEVANCE: Disruption of epididymal function and therefore, male infertility, will arise as a consequence of abnormal fetal development. Therefore, it is important to examine and understand the causes of congenital defects that lead to male infertility. Further, understanding the development and growth of the epididymis will provide fundamental information as to why this organ rarely succumbs to cancer.

描述（由申请人提供）：附加膜，尤其是初始部分，在精子的成熟中起重要作用，并且没有完全开发的初始段，男性不孕将导致。该提议的中心假设是附睾功能的缺陷是由异常的初始片段发展引起的，并考虑到人类附子具有初始段样上皮，因此了解该区域的发展很重要。我们对了解调节这种重要器官发展的机制特别感兴趣，因为由于异常发育而导致对附睾功能的破坏也可能出现。因此，在此应用中，在理解发育过程中细胞增殖的调节时会溢价。尽管雄激素调节附生的发育，但假设发光因子（睾丸腔流体因子）起主要作用。这是一个新颖的假设，因为发光因素仅与保护初始片段免受凋亡的保护有关。此外，应用程序中概述的实验将挑战教条 细胞增殖在产后没有差异化调节。我们的工作假设是，随着发光因素从产后调节细胞增殖转变为调节成年后的细胞存活，细胞从增殖状态转移到非增殖状态。这是通过通过上游发光液生长因子配体在初始段细胞的顶膜上与它们的同源受体相互作用来调节特定信号通路来实现的，从而确保形成完全开发且正常运行的初始段。为了检验该假设，提出了三个具体目的：（1）测试以下假设：在产后期间，在时间窗口内，发光因素调节初始片段细胞的增殖，以测试腔腔FGF和下游信号的腔内途径的介绍在介导的途径的表达中，该假说在跨度途径的表达（3）调节后的初始初始段（3） FGF/FGFR/PI3K/AKT/MTOR途径是细胞增殖所必需的，TOFGF/FGFR/PERK/PMEK途径是细胞保护所必需的，这是PTEN上调，激活和/或在最初片段发育期间特定阶段的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鲜为人知的生殖生物学领域产生重大影响，而且还将有助于我们理解导管/管伸长的基本过程。具体而言，他们将对一个附睾特异性区域的发展在临床上是重要的，以及在发育过程中附睾增长的调节如何有助于我们理解为什么附睾很少屈服于癌症。 公共卫生相关性：附睾功能的破坏，因此，由于胎儿发育异常，将出现男性不育症。因此，重要的是检查和理解导致男性不育症的先天性缺陷的原因。此外，了解附睾的发展和生长将提供有关为什么这种器官很少屈服于癌症的基本信息。