Discovery & Function of Fertilization-Specific Molecules

描述（由申请人提供）：人口继续以惊人的速度增长，使得开发更安全、更经济和更有效的避孕药具成为与健康有关的重要目标。在Henry J. Kaiser家庭基金会1997年的一项调查中，超过66%的受访者认为男性应该在避孕方面发挥更大的作用。干预受精的能力可以帮助想要孩子的夫妇，提高濒危物种或作为食物来源的家畜的繁殖效率，并降低某些野生动物种群（如害虫）的受精率，使数百万人的健康受益。然而，受精过程仍然知之甚少，导致干预方法的发展受到严重限制。该项目的总体目标是确定对精子行为和受精至关重要的基因。基因的初始选择标准依赖于编码预测精子受体、通道、转运蛋白、粘附蛋白、转位酶或离子交换剂的蛋白质的cDNA序列，以及在减数分裂期间或之后精子中只表达的基因。具体目标1集中于发现和功能分析新的精子候选基因（凝集素样基因，单一TM潜在受体，趋化因子样四联蛋白）。它们将成为干扰的目标，以确定对精子行为和生育能力的影响。基因产物将被研究以确定调控机制。研究人员将继续寻找对生育能力至关重要的新候选基因，并将描述精子特异性钠/氢交换器（sNHE）在顶体反应的获能和诱导中的作用。Specific Aim 2是对候选基因产物调控的详细分析。sNHE将作为其他候选基因产物的主要原型。研究将集中于sNHE的调控机制（如共价修饰和相关蛋白对sNHE活性的影响）。基于这些研究，连锁图谱将开始连接sNHE或其他候选基因产物与精子行为反应（如运动激活或顶体反应的诱导）的途径。

DESCRIPTION (provided by applicant): The human population continues to expand alarming rates making the development of safer, more economical and effective contraceptives an important health-related goal. In a 1997 survey by the Henry J. Kaiser Family Foundation, more than 66% of respondents believed that men should play a larger role in contraceptive use. The ability to intervene in fertilization could aid couples wanting children, increase reproductive efficiency in endangered species or domestic animals used as food sources, and decrease fertilization rates of certain wild animal populations such as vermin, benefiting the health of millions of people. However, the fertilization process remains poorly understood, leading to severe limitations in development of methods to intervene. The over-all goal of this project is to identify genes critical to sperm behavior and fertilization. The criterion for initial selection of genes relies on cDNA sequences encoding proteins that predict a sperm receptor, channel, transporter, adhesion protein, translocase or ion exchanger, and on genes expressed exclusively in spermatozoa during or after meiosis. Specific Aim 1 centers on the discovery and functional analysis of new sperm candidate genes (lectin-like, single TM potential receptor, chemokine-like tetraspan). They will be targeted for disruption to determine the effects on sperm behavior and fertility. The gene products will be studied to define mechanisms of regulation. Searches will continue for new candidate genes critical to fertility, and the role of a sperm-specific sodium/hydrogen exchanger (sNHE) in capacitation and induction of the acrosome reaction will be delineated. Specific Aim 2 is a detailed analysis of candidate gene product regulation. The sNHE will serve as the primary prototype for other candidate gene products. Studies will concentrate on mechanisms of regulation of the sNHE (e.g. the effects of covalent modification and associated proteins on sNHE activity). Based on these studies, linkage maps will begin to connect pathways from the sNHE, or other candidate gene products, to sperm behavioral responses such as motility activation or induction of the acrosome reaction.