ROLE OF ACTIN CYTOSKELETON DURING MOUSE SPERM ACROSOMAL EXOCYTOSIS

描述(申请人提供)：哺乳动物精子必须经历一个称为获能的过程，才能使卵子受精。获能使精子有能力通过启动细胞来经历一种称为顶体胞吐的快速事件，这是由卵子或黄体酮的骨质带(ZP)刺激的。多年来，一些生化事件与获能过程有关；然而，在获能研究中仍未回答的问题是：是什么潜在的反应或一系列反应将精子细胞从对ZP或黄体酮刺激的顶体胞吐反应无效的状态转变为对这些刺激准备反应的状态？我们的初步结果表明，肌动蛋白细胞骨架在这一过程中发挥了作用。我们这项研究的长期目标是：阐明肌动蛋白细胞骨架控制哺乳动物精子顶体胞吐的分子机制。在这项建议中，我们评估了精子获能过程中顶体胞吐的启动状态的建立和稳定。此外，我们还将研究细胞内钙和肌动蛋白在顶体胞吐启动状态的不稳定中的作用，顶体外膜和质膜的融合是导致顶体外膜和质膜融合的原因。这些研究具有重要意义，有几个与人类健康相关的原因。例如，了解这一过程可能会更好地理解某些男性不育病例，并开发出干预这一过程的药理学方法，从而产生新的避孕药。最重要的是，由于肌动蛋白与许多类型的体细胞发生的胞吐有关，从不太复杂的精子系统中收集的信息可能会影响我们对内分泌或消化组织等其他器官系统分泌的理解。 公共卫生相关性：在这项应用中，我们将有助于阐明哺乳动物精子中肌动蛋白细胞骨架控制顶体胞吐的分子机制。研究顶体胞吐可能会导致更好的方法来治疗某些男性不育病例，并开发新的避孕药。从研究精子系统收集的信息将影响我们对内分泌或消化组织等其他器官系统分泌的理解。

DESCRIPTION (provided by applicant): Mammalian sperm must undergo a process termed capacitation to become competent to fertilize an egg. Capacitation renders the sperm competent by priming the cells to undergo a rapid exocytotic event called acrosomal exocytosis that is stimulated by the zona pelucida (ZP) of the egg or progesterone. Over the years, several biochemical events have been associated with the capacitation process; however, the question that has remained unanswered in investigations of capacitation is: What is the underlying reaction or set of reactions that transform the sperm cell from a state unresponsive to ZP or progesterone-stimulated acrosomal exocytosis to the state primed to respond to these stimuli? Our preliminary results demonstrate that the actin cytoskeleton plays a role in this process. Our long-term goal of this research: to elucidate the molecular mechanism whereby the actin cytoskeleton controls acrosomal exocytosis in mammalian sperm. In this proposal, we evaluate the establishment and stabilization of the primed state of acrosomal exocytosis that develops during the course of sperm capacitation. Additionally, we will examine the roles of intracelular calcium and actin in the destabilization of the primed state of acrosomal exocytosis that results in the propagation of the fusion of the outer acrosomal and plasma membranes. There are several human health-related reasons these studies are significant. For example, an understanding this process may lead to a better understanding of certain cases of male infertility and to the development of pharmacological approaches to interfere with this process, leading to new contraceptive agents. Most importantly, since actin has been implicated in exocytosis occurring in many types of somatic cells, information gathered from studying the less complicated sperm system will likely impact our understanding of secretion in other organ systems such as endocrine or digestive tissues. PUBLIC HEALTH RELEVANCE: In this application, we will contribute to elucidate the molecular mechanism whereby the actin cytoskeleton controls acrosomal exocytosis in mammalian sperm. Investigating acrosomal exocytosis may lead to better approaches to certain cases of male infertility and to the development of new contraceptive agents. Information gathered from studying the sperm system will impact our understanding of secretion in other organ systems such as endocrine or digestive tissues.