Regulators of the sperm acrosome reaction

描述（由申请人提供）：精子和卵子在受精时的结合是生殖的重要步骤。在哺乳动物中，包括人类，精子必须首先与卵细胞结合，并在与卵细胞融合之前完成顶体反应。透明质酸通过TRPC通道驱动钙离子进入精子，从而启动顶体反应。然而，透明质酸通过这些精子离子通道调节电导的机制知之甚少，是我们知识中的一个主要空白。基于初步和已发表的数据，提出了一个工作假设，即透明质酸驱动磷脂酰肌醇-4，5-二磷酸（PIP 2）的合成，并且这种脂质通过两种不同的机制调节TRPC通道家族的两个成员的功能。本提案的目的是：1）确定透明质酸调节PIP 2合成和代谢的机制; 2）确定PIP 2通过TRPC通道控制钙电导的机制; 3）确定精子获能和精浆组分如何促进TRPC通道功能和受精。这些研究在两个方面具有相关性。首先，它们可能会促进我们对受精的基本生物学的理解。第二，这些研究可能对治疗人类不育症和设计新型避孕药产生治疗效果。特别地，响应于透明质酸刺激而在精子中产生的PIP 2代谢物的作用与人类顶体反应的控制直接相关。

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.