Molecular and genetic mechanisms of sperm capacitation

精子获能的分子和遗传机制

• 批准号: 8081157
• 负责人: Harvey M Florman
• 金额: $ 3.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-28 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081157
• 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; 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; TRP channel; 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

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）：哺乳动物的精子是由雄性在不育状态下释放的，并获得了通过生理重编程或“电容”施肥的能力，该生殖道发生在女性生殖道中。电容与精子的生化和生物物理特性中的各种修饰有关，并导致该细胞行为库的各种变化。但是，可用的证据表明电容不是一个统一事件，而是一系列成分反应的总和，这些反应在时间过程中和调节方式上有所不同。目前的挑战以及这个新项目的长期小马驹是准备精子信号转导的链接图，其中特定的成分反应与上游激活剂和下游功能变化有关。该阶段的重点是pkdrej，一种多囊这蛋白在电容中的作用。 PKDREJ基因的靶向缺失产生了能力的某些方面的减慢，以及精子对卵形流体的化学感应反应的失败。据信，多囊蛋白-1蛋白充当激活信号通路的配体或机械激活的受体。在精子中提出了类似的作用，其中PKDREJ充当电容信号的受体。这项工作的第一阶段的具体目的是：1）确定介导PKDREJ信号转导的细胞内效应子； 2）确定PKDREJ控制精子内pH升高的机制； 3）分析PKDREJ的运动调节机制； 4）在电容期间以pkdrej依赖性方式鉴定精子蛋白。该项目的公共卫生意义在两个相关领域。在一个潜在的灾难性人口增长的时代，有必要确定避孕的新策略。鉴于电容在受精中的重要作用，因此希望受体介导的电容途径可以提供多个目标。同样，电容失败会导致不孕症，这影响了美国夫妻至10％，并且对相关途径的新知识可能会导致新的治疗策略。 Publice Health相关性：该项目重点介绍了Polycystin-1家庭成员PKDREJ对精子电容的控制。电容是受精过程中的强制性事件，对潜在机制的洞察力可以帮助控制飙升的人群，现在在全球范围内超过67亿，并且提供了不育的新方法，估计在美国影响10-15％的夫妇。