Regulators of the sperm acrosome reaction

精子顶体反应的调节者

• 批准号: 8116075
• 负责人: Harvey M Florman
• 金额: $ 31.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116075
• 关键词: Acrosome; Acrosome Reaction; Affect; Agonist; Automobile Driving; Behavioral; Binding; Biochemical; Biological Assay; Biology; Calcium; Cations; Cells; Chromosome Mapping; Contraceptive Agents; Couples; Coupling; Cytoplasmic Granules; Data; Electrophysiology (science); Event; Exocytosis; Family; Fertilization; Genes; Glycoproteins; Goals; Herpes zoster disease; Human; Image; Infertility; Ion Channel; Knowledge; Lead; Life; Link; Lipids; Mammals; Maps; Metabolism; Modeling; Molecular; Mus; Pathway interactions; Phase; Phosphatidylinositol 4,5-Diphosphate; Population; Population Control; Process; Publishing; Reproduction; Role; Route; Secretory Vesicles; Seminal; Seminal Plasma; Signal Pathway; Signal Transduction; Sperm Capacitation; Sperm Maturation; Staging; Systems Biology; Testing; Therapeutic; Wild Type Mouse; Work; Zona Pellucida; base; design; egg; inhibitor/antagonist; insight; member; novel; patch clamp; receptor; response; sperm cell; sperm function; zona pellucida glycoprotein

DESCRIPTION (provided by applicant): The union of sperm and egg at fertilization is an essential step in reproduction. In mammals, including human, sperm must first bind to the egg zona pellucida and complete the acrosome reaction before fusing with the egg. The zona pellucida initiates acrosome reactions by driving calcium entry into sperm through TRPC channels. However, the mechanisms by which the zona pellucida regulates the conductance through these sperm ion channels are poorly understood and represent a major gap in our knowledge. Based on preliminary and published data, a working hypothesis is developed that the zona pellucida drives the synthesis of phosphatidylinositol-4, 5-bisphosphate (PIP2) and that this lipid regulates the function of two members of the TRPC channel family by two distinct mechanisms. The aims of this proposal are to: 1) determine the mechanism by which the zona pellucida regulates PIP2 synthesis and metabolism; 2) determine the mechanisms by which that PIP2 controls calcium conductance through TRPC channels; and 3) determine how sperm capacitation and seminal plasma components contribute to TRPC channel function and to fertilization. These studies are relevant in two regards. First, they may advance our understanding of the basic biology of fertilization. Second, there may be therapeutic consequences of these studies both with regard to the treatment of human infertility and for the design of novel contraceptives. In particular, the effects of PIP2 metabolites that are produced in sperm in response to zona pellucida stimulation are directly relevant to the control of the human acrosome reaction.

描述（由申请人提供）：受精时精子和鸡蛋结合是生殖的重要步骤。在包括人在内的哺乳动物中，精子必须首先与卵佐那蛋黄酱结合，并在与鸡蛋融合之前完成ACROSOM反应。 Zona pellucida通过通过TRPC通道将钙进入精子进入精子来启动ACROSOM反应。但是，Zona Pellucida通过这些精子离子通道调节电导的机制知之甚少，在我们所知中代表了一个主要差距。基于初步和已发布的数据，开发了一个工作假设，即Zona pellucida驱动磷脂酰肌醇-4、5-双磷酸（PIP2）的合成，并且该脂质调节了两个不同机制的两个TRPC通道家族成员的功能。该提议的目的是：1）确定Zona Pellucida调节PIP2合成和代谢的机制； 2）确定PIP2通过TRPC通道控制钙电导的机制； 3）确定精子电容和精液等离子体成分如何有助于TRPC通道功能和受精。这些研究在两个方面都相关。首先，他们可能会促进我们对受精的基本生物学的理解。其次，这些研究在人类不孕症的治疗和新颖避孕药的设计方面可能会产生治疗后果。特别是，响应于Zona pellucida刺激而在精子中产生的PIP2代谢产物的作用与控制人类坡道反应的控制直接相关。