Regulators of the sperm acrosome reaction

描述（由申请人提供）：受精时精子和卵子的结合是生殖和发育的重要步骤。在包括人类在内的哺乳动物中，精子必须首先与卵子的透明带外壳结合并完成顶体反应，然后才能与卵子融合。透明带通过触发钙离子通过TRPC阳离子通道进入精子，从而引发顶体反应。然而，将钙信号耦合到顶体反应的最终事件的下游机制尚不清楚，这代表了我们对受精的理解中的一个主要空白。

DESCRIPTION (provided by applicant): The union of sperm and egg at fertilization is an essential step in reproduction and development. In mammals, including human, sperm must first bind to the egg's zona pellucida coat and complete the acrosome reaction before fusing with the egg. The zona pellucida initiates acrosome reactions by triggering the entry of calcium ions into sperm through TRPC cation channels. However, the downstream mechanisms that couple calcium signals into the final events of the acrosome reaction are poorly understood and represent a major gap in our understanding of fertilization. We discovered a novel TRPC binding protein, enkurin, in sperm. The objective of this project is to delineate the roles of enkurin in sperm function. The working hypotheses for this stage of the project is that enkurin is an adaptor that acts by tethering regulatory molecules to the TRPC channel, and that these regulatory molecules play essential roles in the initiation of the acrosome reaction. These hypotheses will be tested in experiments that: (i) map interaction sites on enkurin for TRPC channels and a regulatory kinase that mediate binding and functional activity; (ii) identify products of the activated regulatory kinase in sperm; (iii) determine the downstream consequences of enkurin/kinase activation in control of acrosome reactions; (iv) determine, the mechanism by which enkurin regulates TRPC ion channel activity; and (v) determine the mechanism of enkurin action in transgenic mice. These studies are relevant in two regards. First, they may advance our basic understanding of an essential step in the reproductive process. Second, there may be therapeutic consequences to these studies both with regard to the treatment of human infertility and for the design of new contraceptives.