Molecular and genetic mechanisms of sperm capacitation

精子获能的分子和遗传机制

基本信息

批准号：
8305704
负责人：
Harvey M Florman
金额：
$ 33.22万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305704
关键词：
Affect Alleles Area Behavior Behavioral Binding Biochemical C-terminal Cations Cells Chemotaxis Chromosome Mapping Complex Contraceptive methods Coupled Couples Coupling Defect Event Exhibits Failure Family Family member Female Fertility Fertilization Gene Mutation Genes Goals Health In Vitro Infertility Knockout Mice Knowledge Laboratories Lead Ligands Link Liquid substance Mammalian Oviducts Maps Mass Spectrum Analysis Mechanics Mediating Methods Modification Molecular Genetics Mus Mutation Pathway interactions Phase Phosphoproteins Physiological Population Population Control Population Growth Process Property Proteins Public Health Reaction Regulation Regulatory Pathway Reproduction Role Series Signal Pathway Signal Transduction Speed Sperm Capacitation Sperm Motility Staging Sum Systems Biology Tail Time Tyrosine Tyrosine Phosphorylation Work base cell motility cellular imaging egg image processing in vivo insight male novel novel therapeutics polycystic kidney disease 1 protein programs receptor reproductive response sperm cell sperm protein zygote

项目摘要

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.

描述（由申请人提供）：哺乳动物精子在不育状态下由雄性释放，并通过雌性生殖道发生的生理重编程或“获能”获得受精能力。获能与精子的生化和生物物理特性的多种改变相关，并导致该细胞的行为库的多种变化。然而，现有证据表明，获能不是一个单一事件，而是一系列时间进程和调节模式不同的组成反应的总和。目前的挑战，也是这个新项目的长期目标，是准备精子信号转导的连锁图，其中特定的组分反应与上游激活剂和下游功能变化相关。这一阶段的重点是 pkdrej（一种多囊蛋白 1 蛋白）在获能过程中的作用。 pkdrej 基因的定向删除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应反应失败。 Polycystin-1 蛋白被认为充当配体或机械激活受体，激活信号通路。精子中也有类似的作用，其中 pkdrej 充当获能信号的受体。这项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子； 2) 确定pkdrej控制精子内部pH升高的机制； 3）分析pkdrej调节运动的机制； 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体现在两个相关领域。在人口增长可能造成灾难性的时代，有必要确定新的避孕策略。鉴于获能在受精中的重要作用，因此希望受体介导的获能途径可以提供多个目标。同样，获能失败会导致不孕症，影响美国超过 10% 的夫妇，对相关途径的新认识可能会带来新的治疗策略。公共健康相关性：该项目重点关注多囊蛋白 1 家族成员 pkdrej 对精子获能的控制。获能是受精过程中的必然事件，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），并提供新的不孕症治疗方法，据估计，不孕症影响了 10-15% 的不孕症患者。在美国的情侣。