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Cyclic Nucleotide-Activated Calcium Channels in Sperm

精子中环状核苷酸激活的钙通道

基本信息

批准号：
8081161
负责人：
Dejian Ren
金额：
$ 6.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-14 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081161
关键词：
Acrosome Reaction Affect Anus Bicarbonates Calcium Calcium Channel CatSper Cell membrane Core Protein Cyclic AMP Cyclic Nucleotides Defect Development Feedback Female Fertility Fertility Agents Fertilization Foundations Future Goals Homologous Gene Hormonal Human Infertility Ion Channel Ions Knock-out Knockout Mice Male Contraceptive Agents Male Infertility Mediating Membrane Modeling Molecular Mus Mutant Strains Mice Mutation Phenotype Phototransduction Physiological Physiology Proteins Regulation Research Role Sperm Capacitation Sperm Maturation Sperm Motility Sperm Tail Sperm Transport Spermatids Spermatocytes Spermatogenesis Staging Sterility Testing Testis Zona Pellucida cell motility cyclic-nucleotide gated ion channels drug development egg male mutant novel programs protein complex protein expression reproductive response sperm cell sperm function synergism

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research is to understand the sperm function regulation by calcium, cyclic nucleotides and ion channels at the molecular level. This proposal focuses on the roles of a sperm tail ion channel (CatSper1) we discovered. CatSper1 from human and mice is only expressed in testis. The protein in sperm is strikingly localized in the principal piece membrane. Mice deficient in CatSper1 show no gross phenotypes except that males are completely infertile. The cyclic AMP-induced calcium influx into sperm is deficient in CatSper1-null mice. Because of its restricted protein expression in sperm tail and because of its restricted knockout phenotype in male fertility, CatSper1 represents an excellent target for safe non-hormonal male contraceptives. Aim 1 will determine the physiological roles of CatSper1 in male fertility. CatSper1-deficient males will be examined in detail and the reason(s) for male infertility will be determined. Aim 2 will uncover the molecular mechanism underlying the CatSper1 function regulation during spermatogenesis and sperm maturation. Four hypotheses will be tested: a. the CatSper1 protein expression is regulated; b. the protein's plasma membrane localization is regulated; c. the protein is modified; and d. the composition of the channel core protein complex is modulated. Aim 3 will test the current model concerning the roles of the cyclic nucleotide-gated (CNG) ion channels in the sperm cAMP-induced calcium influx. Aim 4 will test the hypothesis that the CatSper1 channel mediates a "cAMP- calcium positive feedback loop" in that cAMP causes calcium influx through the channel and the resulting calcium increase, in turn, causes cAMP to rise. Results from this study will allow us to understand the ion mechanism underlying sperm motility and may lay the foundation for the future development of drugs for infertility treatment and for male contraceptives.

描述（申请人提供）：本研究的总体目标是在分子水平上了解钙、环核苷酸和离子通道对精子功能的调节。这项建议的重点是我们发现的精子尾离子通道（CatSper 1）的作用。人和小鼠的CatSper 1仅在睾丸中表达。精子中的蛋白质明显地定位于主膜中。CatSper 1缺陷小鼠除了雄性完全不育外，没有表现出明显的表型。CatSper 1基因敲除小鼠中cAMP诱导的钙离子内流不足。由于其在精子尾部的限制性蛋白表达和由于其在男性生育力中的限制性敲除表型，CatSper 1代表了安全的非激素男性避孕药的极好靶点。目的1：明确CatSper 1在男性生育中的生理作用。将详细检查CatSper 1缺陷的男性，并确定男性不育的原因。目的2揭示CatSper 1在精子发生和成熟过程中功能调控的分子机制。将测试四个假设：a。CatSper 1蛋白表达受到调节; B.所述蛋白质的质膜定位受到调节; c.所述蛋白质被修饰;以及d.调节通道核心蛋白复合物的组成。目的3：验证环核苷酸门控（CNG）离子通道在cAMP诱导的精子钙内流中的作用。目的4将检验CatSper 1通道介导“cAMP-钙正反馈环”的假设，因为cAMP导致钙通过通道内流，并且由此产生的钙增加反过来导致cAMP升高。这项研究的结果将使我们能够了解精子运动的离子机制，并可能为未来开发治疗不孕症的药物和男性避孕药奠定基础。