Molecular and genetic mechanisms of sperm capacitation

描述（由申请人提供）：哺乳动物精子由不育状态的雄性动物释放，并通过生理重编程或“获能”获得受精能力，这发生在雌性生殖道中。获能与精子的生物化学和生物物理特性的不同修饰相关，并导致该细胞的行为库的不同变化。然而，现有的证据表明，获能不是一个单一的事件，而是一系列不同的时间过程和调节模式的组件反应的总和。目前的挑战，这个新项目的长期马驹，是准备一个精子信号转导的连锁图，其中特定的组件反应相关的上游激活剂和下游的功能变化。这一阶段的重点是pkdrej，多囊蛋白-1蛋白，在获能的作用。pkdrej基因的靶向缺失导致获能选择方面的减缓和精子对输卵管液的化学感受性反应的失败。多囊蛋白-1蛋白被认为作为激活信号传导途径的配体或机械激活的受体起作用。在精子中也有类似的作用，pkdrej作为获能信号的受体。本研究第一阶段的具体目标是：1）鉴定介导pkdrej信号转导的细胞内效应物; 2）确定pkdrej控制精子内部pH升高的机制; 3）分析pkdrej调节精子运动的机制; 4）鉴定获能过程中以pkdrej依赖性方式磷酸化的精子蛋白。该项目的公共卫生意义体现在两个相关领域。在一个人口增长可能带来灾难性后果的时代，有必要确定新的避孕战略。鉴于获能在受精中的重要作用，人们希望受体介导的获能途径可以提供几个靶点。类似地，获能失败导致不孕，这影响了美国>10%的夫妇，相关途径的新知识可能会导致新的治疗策略。公共卫生相关性：该项目的重点是多囊蛋白-1家族成员pkdrej对精子获能的控制。获能是受精过程中的一个强制性事件，深入了解其潜在机制有助于控制人口激增，目前全球人口已超过67亿，并为不孕症提供新的治疗方法，据估计，美国有10-15%的夫妇受到影响。

DESCRIPTION (provided by applicant): Mammalian sperm are released by the male in an infertile state, and acquire the ability to fertilize through a physiological reprogramming, or "capacitation", which occurs with the female reproductive tract. Capacitation is associated with diverse modifications in the biochemical and biophysical properties of sperm, and leads to diverse changes in the behavioral repertoire of that cell. However, available evidence indicates that capacitation is not a unitary event, but instead is the sum of a series of component reactions that differ in time course and in mode of regulation. The challenge at present, and the long-term foal of this new project, is to prepare a linkage map of sperm signal transduction, in which specific component reactions are related to upstream activators and to downstream functional changes. This phase focuses on the role of pkdrej, a polycystin-1 protein, in capacitation. Targeted deletions of the pkdrej gene produce a slowing of select aspects of capacitation and in the failure of a chemosensory response of sperm to oviduct fluid. Polycystin-1 proteins are believed to function as ligand- or mechanically-activated receptors that activate signaling pathways. A similar role is proposed in sperm, in which pkdrej acts as a receptor for a capacitating signal. The specific aims for the first stage of this work are: 1) to identify intracellular effectors that mediate pkdrej signal transduction; 2) to determine the mechanism by which pkdrej controls the elevation of sperm internal pH; 3) to analyze the mechanism of motility regulation by pkdrej; and 4) to identify the sperm proteins that are phosphorylated in a pkdrej-dependent manner during capacitation. The public health significance of this project is in two related areas. In an era of potentially catastrophic population growth it is necessary to identify new strategies of contraception. Given the essential role of capacitation in fertilization, then it is hoped that a receptor-mediated capacitation pathway may provide several targets. Similarly, failures of capacitation contribute to infertility, which effects >10% of couples in the US, and new knowledge of the relevant pathways may lead to novel therapeutic strategies. PUBLICE HEALTH RELEVANCE: This project focuses on the control of sperm capacitation by pkdrej, a polycystin-1 family member. Capacitation is an obligatory event in the fertilization process and insight into the underlying mechanisms can help to control soaring population, which now exceeds 6,700 million world-wide, as well as provide novel treatments of infertility, which is estimated to affect 10-15% of couples in the US.