Lumicrine regulation of epididymal function

描述（由申请方提供）：附睾的起始段功能是维持一个专门的管腔液体环境，这对精子成熟和男性生育力至关重要。起始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，起始段会发生细胞凋亡并无法发挥功能。因此，本研究将探讨睾丸腔液因子调节起始段功能的机制。我们发表的和初步研究的结果使我们能够制定“光泌”假说：支持细胞和/或生殖细胞来源的生长因子进入曲细精小管的管腔，通过睾丸网和输出管流出睾丸，进入附睾管并与位于起始段细胞顶面的同源受体相互作用。在这里，第二信使途径被激活，这导致转录因子的激活和基因的反式激活。这些基因对于（1）保护初始片段免于凋亡和（2）保护成熟精子免于氧化应激并为其成熟提供专门的腔液微环境是重要的。该提案将专门侧重于研究睾丸腔液生长因子的作用，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，参与初始段功能，因此男性生育力。具体而言，建议：（1）检验管腔FGF和神经营养因子维持促存活途径和保护基因在起始节段中的表达的假设。(2)为了检验活性FGF受体FGFR 111 c和神经营养因子受体复合物TrkC/p75维持促存活途径和保护基因的表达的假设，所述受体复合物对初始节段的主要细胞是特异性的。(3)为了检验FGFR 1 IIIc和TrkC/p75受体的激活由衔接蛋白FGF受体底物2（FRS 2/SNT 1）调节，并且对于维持促存活途径和保护基因的表达是必需的这一假设。(4)以检验初始区段中正常的FGFR 1 IIIc和TrkC/p75受体功能对男性生育力重要的假设。这一提议是长期目标的一部分，以了解附睾维持精子成熟和存活的最佳管腔微环境的机制，从而提高男性生育力。

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.