HCO3 and Na+ transport in human & pig vas deferens

描述（由申请人提供）：该项目的长期目标是确定远端男性生殖道内上皮离子运输途径和相关调控机制，以便为更好地理解生殖功能障碍提供基础。远端输精管（dDD）内的离子运输过程尚未明确，尽管管道内的错误离子运输与弱精子症、少精子症、非阻塞性无精子症和阻塞性无精子症明显相关。最近的观察表明，在dDD中存在一种新的依赖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。我们假设dDD上皮中的特定细胞能够调节Na+依赖性HCO3-分泌和/或Na+吸收。这些过程可以在单独的细胞群中独立发生，也可以在单个细胞群中同时表达。提出的上皮模型代表了目前关于dDD功能的观点的范式转变。这种新的上皮细胞模型提供了神经递质依赖机制，在射精前急性碱化管腔以激活精子，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、生化、细胞化学和分子技术将被用于研究天然上皮和原代细胞培养，以描绘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。

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).