HCO3 and Na+ transport in human & pig vas deferens

描述(申请人提供)：该项目的长期目标是确定男性生殖道远端的上皮离子转运途径和相关的调节机制，以便为更好地了解生殖功能障碍提供基础。输精管远端(DDD)内的离子转运过程尚未明确，尽管导管内的离子转运错误明显与弱精子症、少精子症、非梗阻性无精子症和梗阻性无精子症有关。最近的观察表明，在DDD内存在一种新的依赖于Na+的离子传输途径。这些观察的细胞和分子基础仍有待确定。我们推测，DDD上皮中的特定细胞能够调节Na+依赖的HCO3-分泌和/或Na+吸收。这些过程可以在单独的细胞群体中独立发生，也可以在单个细胞群体中同时表达。提出的上皮模型代表了从目前关于DDD功能的观点的范式转变。这种新的上皮模型提供了神经递质依赖的机制，在射精前将管腔急剧碱化以激活精子，并为解释目前被诊断为特发性的男性因素不育提供了基础。现代电生理学、生化、细胞化学和分子技术将与原代细胞培养一起研究天然上皮，以描述促进上皮功能的机制和信号通路，最终目标是调节男性生育能力。这些假设将通过解决以下具体目标来检验。 目的1.确定HC03跨输精管远端输卵管转运的关键机制。 目的2.确定钠跨输精管远端上皮细胞转运的关键机制。 这些研究的结果将导致对男性生殖道功能的更多了解，以及对NAV和HCO3一般转运机制的更全面的了解。拟议的研究将为治疗男性不育症和调节男性生育能力(即男性避孕)的治疗干预提供合理的基础，从而最终使医学界受益。

DESCRIPTION (provided by applicant): The long-term goal for this project is to determine the epithelial ion transport pathways and the associated regulatory mechanisms within the distal male genital tract in order to provide a basis for better understanding reproductive dysfunction. Ion transport processes within the distal ductus deferens (dDD) have not been clearly identified although errant ion transport within the duct is clearly associated with asthenozoospermia, oligozoospermia, non-obstructive azoospermia, and obstructive azoospermia. Recent observations point to a novel constellation of Na+-dependent ion transport pathways within the dDD. The cellular and molecular basis of these observations remains to be determined. We hypothesize that specific cells in dDD epithelium are capable of regulated Na+-dependent HCO3- secretion and/or Na + absorption. These processes may occur independently in separate cell populations or may be simultaneously expressed in a single cell population. The epithelial model that is proposed represents a paradigm shift from currently held views regarding dDD function. This new epithelial model provides for neurotransmitter-dependent mechanisms to acutely alkalinize the lumen for sperm activation just prior to ejaculation and provides a basis to account for male factor infertility that is currently diagnosed as 'idiopathic.' Modem electrophysiological, biochemical, cytochemical, and molecular techniques will be employed to study native epithelium along with primary cell cultures to delineate the mechanisms and signaling pathways that contribute to epithelial function with the ultimate goal of modulating male fertility. The hypotheses will be tested by addressing the following specific aims. Aim 1. To identify key mechanisms that contribute to HC03 transport across distal ductus deferens pithelia. Aim 2. To identify key mechanisms that contribute to Na vtransport across distal ductus deferens epithelia. Results from these studies will lead to an increased understanding of male reproductive tract function along with a more complete understanding of Nav and HCO3 transport mechanisms in general. The proposed studies will ultimately benefit the medical community by providing rational bases for therapeutic interventions both to treat male infertility and to modulate male fertility (i.e., male contraception).