Lumicrine regulation of epididymal function

描述(申请人提供)：附睾体的起始段的功能是维持一种特殊的管腔液体环境，这对精子成熟和男性生育至关重要。起始段功能的关键调节因素是睾丸腔液因子，如果没有这些因素，起始段就会经历细胞凋亡，从而无法发挥作用。因此，这项建议将解决睾丸腔液因子调节起始节段功能的机制。我们已发表的研究和初步研究的结果使我们得以提出“鲁米克林”假说：生长因子从支持细胞和/或生殖细胞起源，进入生精小管腔，通过睾丸网和传出管排出睾丸，进入附睾管，并与位于起始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，从而导致转录因子的激活和基因的反式激活。这些基因对于(1)保护精子起始段免受细胞凋亡和(2)保护成熟精子免受氧化应激，并为其成熟提供专门的腔内微环境是重要的。该提案将专门研究睾丸腔液生长因子，如成纤维细胞生长因子(成纤维细胞生长因子)家族和神经营养因子家族的成员，在调节基因和信号转导通路中的作用，这些基因和信号转导通路涉及初始段功能，从而影响男性生育能力。具体地说，建议：(1)检验腔内FGFs和神经营养因子维持支持生存通路和保护基因在起始节段的表达的假设。(2)验证FGFR1Illc活性受体和神经营养因子受体复合体TrkC/p75是起始节段主细胞所特有的，维持促生存通路和保护性基因表达的假说。(3)验证FGFR1I11c和TrkC/p75受体激活受FGFR2/SNT1受体底物2(FRS2/SNT1)调节的假设，这是维持促生存通路和保护基因表达所必需的。(4)验证FGFR1I11c和TrkC/p75受体功能正常对男性生育能力有重要影响的假说。这一建议是长期目标的一部分，目的是了解附睾维持精子成熟和存活以及男性生育能力的最佳管腔微环境的机制。

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.