HCO3 and Na+ transport in human & pig vas deferens

描述（由申请人提供）：本项目的长期目标是确定远端男性生殖道内的上皮离子转运途径和相关调控机制，以便为更好地了解生殖功能障碍提供基础。远端输精管（DDD）内的离子转运过程尚未明确确定，尽管导管内的错误离子转运明显与弱精子症、少精子症、非梗阻性无精子症和梗阻性无精子症相关。最近的观察指出，一个新的星座的Na+依赖性离子转运途径内的DDD。这些观察结果的细胞和分子基础仍有待确定。我们假设，特定的细胞在DDD上皮细胞能够调节Na+依赖性HCO 3-分泌和/或Na +吸收。这些过程可以在单独的细胞群中独立地发生，或者可以在单个细胞群中同时表达。上皮模型，提出了一个范式转变，从目前持有的观点DDD功能。这种新的上皮模型提供了神经递质依赖性机制，以在射精前急性碱化管腔以激活精子，并提供了解释目前诊断为“特发性”的男性因素不育症的基础。“现代电生理学、生物化学、细胞化学和分子技术将用于研究天然上皮沿着原代细胞培养，以描绘有助于上皮功能的机制和信号通路，最终目标是调节男性生育力。将通过解决以下具体目标来检验假设。 目标1.确定有助于HC 03穿过远端输精管髓部转运的关键机制。 目标2.确定有助于钠转运通过远端输精管上皮的关键机制。 这些研究的结果将导致对雄性生殖道功能的理解增加，沿着对Nav和HCO 3转运机制的理解也更全面。拟议的研究最终将使医学界受益，为治疗男性不育症和调节男性生育能力的治疗干预措施提供合理的基础（即，男性避孕）。

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).