Molecular and genetic mechanisms of sperm capacitation

描述（由申请人提供）：哺乳动物的精子由雄性在不育状态下释放，并通过生理上的重新编程或“获能”获得受精能力，这发生在雌性生殖道中。获能与精子生物化学和生物物理特性的各种变化有关，并导致该细胞行为曲目的各种变化。然而，现有证据表明，能化不是一个单一的事件，而是一系列在时间进程和调节模式上不同的组分反应的总和。目前的挑战，也是这个新项目的长期目标，是准备一个精子信号转导的连锁图谱，其中特定的成分反应与上游的激活剂和下游的功能变化有关。这一阶段的重点是pkdrej（一种多囊蛋白-1蛋白）在获能中的作用。pkdrej基因的定向缺失会导致获能的某些方面减慢，并导致精子对输卵管液体的化学感觉反应失效。多囊蛋白-1被认为是作为配体或机械激活的受体，激活信号通路。在精子中也有类似的作用，pkdrej作为一个赋能信号的受体。本工作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调控精子内部pH值升高的机制；3)分析pkdrej调控运动的机制；4)鉴定在获能过程中以pkdrej依赖性方式磷酸化的精子蛋白。该项目的公共卫生意义在于两个相关领域。在一个潜在的灾难性人口增长的时代，有必要确定新的避孕策略。考虑到能化在受精中的重要作用，我们希望受体介导的能化途径能够提供多种靶点。同样，失能导致不孕，在美国有10%的夫妇受其影响，对相关途径的新认识可能会导致新的治疗策略。公共卫生相关性：本项目重点研究多囊素-1家族成员pkdrej对精子能性的控制。使能是受精过程中必须发生的事件，对潜在机制的深入了解可以帮助控制不断飙升的人口，目前全球人口超过67亿，并为不孕症提供新的治疗方法，据估计，美国有10-15%的夫妇受到不孕症的影响。

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.