Discovery & Function of Fertilization-Specific Molecules

发现

• 批准号: 6994427
• 负责人: Timothy A Quill
• 金额: $ 30.85万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994427
• 关键词: acrosome; biological signal transduction; fertility; fertilization; genetic mapping; genetic regulation; genetically modified animals; laboratory mouse; laboratory rabbit; membrane proteins; molecular biology information system; nucleic acid sequence; protein signal sequence; protein structure function; sodium hydrogen exchanger; sperm; sperm capacitation; sperm motility; tissue /cell culture

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.

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一个重要的健康相关目标。在1997年由亨利J.凯泽家庭基金会进行的一项调查中，超过66%的受访者认为男子应该在避孕药具的使用中发挥更大的作用。干预受精的能力可以帮助想要孩子的夫妇，提高濒危物种或用作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，造福数百万人的健康。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。基因初始选择的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仅在精子中表达的基因。具体目标1集中在新的精子候选基因（凝集素样，单一TM潜在受体，趋化因子样tetraspan）的发现和功能分析。它们将被作为破坏的目标，以确定对精子行为和生育能力的影响。将研究基因产物以确定调控机制。研究将继续寻找对生育力至关重要的新的候选基因，并将描述精子特异性钠/氢交换器（sNHE）在获能和诱导顶体反应中的作用。具体目标2是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的调节机制（例如共价修饰和相关蛋白质对sNHE活性的影响）。基于这些研究，连锁图谱将开始将sNHE或其他候选基因产物的途径与精子行为反应（如运动激活或诱导顶体反应）联系起来。