Lumicrine regulation of epididymal function

附睾功能的 Lumicrine 调节

• 批准号: 7148538
• 负责人: Barry T. Hinton
• 金额: $ 26.11万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148538
• 关键词: RNA interference; apoptosis; binding proteins; biological signal transduction; cell differentiation; cysteine endopeptidases; cytoprotection; endocrinology; epididymis; fertility; fibroblast growth factor; gene environment interaction; gene expression; genetic regulation; genetic screening; growth factor receptors; laboratory rat; neurotrophic factors; protein structure function; protein tyrosine kinase; semen; sperm; sperm analysis; spermatogenesis; transfection

DESCRIPTION (provided by applicant): The initial segment of the epididymis functions to maintain a specialized luminal fluid environment that is crucial for sperm maturation and therefore male fertility. Key regulators of initial segment function are testicular luminal fluid factors and without these factors the initial segment undergoes apoptosis and fails to function. Therefore, this proposal will address the mechanisms by which testicular luminal fluid factors regulate initial segment function. Findings from our published and preliminary studies allowed us to formulate the "lumicrine" hypothesis: Growth factors, of Sertoli cell and/or germ cell origin, enter the lumen of the seminiferous tubule, pass out of the testis via the rete testis and efferent ducts, enter the epididymal duct and interact with their cognate receptors located on the apical surface of initial segment cells. Here, second messenger pathways are activated, which result in activation of transcription factors and transactivation of genes. These genes are important for (1) protection of the initial segment from apoptosis and (2) protection of maturing spermatozoa from oxidative stress and providing a specialized luminal fluid microenvironment for their maturation. The proposal will focus specifically on examining the role of testicular luminal fluid growth factors, such as members of the fibroblast growth factor (FGF) family and neurotrophin family, in regulating genes and signal transduction pathways that are involved in initial segment function, and therefore male fertility. Specifically, it is proposed: (1) to test the hypothesis that luminal FGFs and neurotrophins maintain the expression of pro-survival pathways and protective genes in the initial segment. (2) to test the hypothesis that active FGF receptor FGFR1 Illc and the neurotrophin receptor complex TrkC/p75, which are specific to the principal cells of the initial segment, maintain the expression of pro-survival pathways and protective genes. (3) to test the hypothesis that activation of FGFR1 Illc and TrkC/p75 receptors is modulated by the adaptor protein FGF receptor substrate 2 (FRS2/SNT1), and is necessary to maintain the expression of pro-survival pathways and protective genes. (4) to test the hypothesis that normal FGFR1 Illc and TrkC/p75 receptor function in the initial segment are important for male fertility. This proposal is part of a long term goal to understand the mechanisms by which the epididymis maintains an optimal luminal microenvironment for sperm maturation and survival, and therefore male fertility.

描述（由申请人提供）：附睾初始段的功能是维持一个特殊的腔液环境，这对精子成熟和男性生育能力至关重要。初始节段功能的关键调节因子是睾丸腔液因子，如果没有这些因子，初始节段就会发生凋亡，无法发挥功能。因此，本研究将探讨睾丸腔液因子调节初始节段功能的机制。我们发表的研究和初步研究的结果使我们能够形成“腔内”假说：支持细胞和/或生殖细胞来源的生长因子进入精小管管腔，通过睾丸网和传出管排出睾丸，进入附睾管并与位于初始节段细胞顶端表面的同源受体相互作用。在这里，第二信使通路被激活，导致转录因子的激活和基因的反激活。这些基因在以下方面很重要：(1)保护起始片段免受细胞凋亡的影响；(2)保护成熟精子免受氧化应激的影响，并为其成熟提供一个专门的腔液微环境。该提案将特别侧重于检查睾丸腔液生长因子（如成纤维细胞生长因子（FGF）家族和神经营养因子家族的成员）在调节基因和信号转导途径中的作用，这些基因和信号转导途径涉及初始节段功能，从而影响男性生育能力。具体而言，我们提出：(1)验证luminal fgf和neurotrophins在初始段维持促生存通路和保护基因表达的假设。(2)验证初始节段主细胞特异性活性FGF受体FGFR1 Illc和神经营养因子受体复合物TrkC/p75维持促存活通路和保护基因表达的假设。(3)验证FGFR1 Illc和TrkC/p75受体的激活是由接头蛋白FGF受体底物2 （FRS2/SNT1）调节的，并且是维持促生存途径和保护基因表达所必需的假设。(4)验证初始段正常的FGFR1 Illc和TrkC/p75受体功能对男性生育能力的重要作用。这一建议是了解附睾维持精子成熟和存活的最佳腔内微环境的机制的长期目标的一部分，因此男性生育能力。