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过程中必不可少的一步。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结合并完成顶体反应，然后才能与卵子融合。透明带通过TRPC通道驱动钙进入精子，从而引发顶体反应。然而，透明带通过这些精子离子通道调节电导的机制尚不清楚，这是我们知识中的一个主要空白。基于初步和已发表的数据，我们提出了一个有效的假设，即透明带驱动磷脂酰肌醇- 4,5 -二磷酸（PIP2）的合成，并且这种脂质通过两种不同的机制调节TRPC通道家族两个成员的功能。本提案的目的是：1)确定透明带调节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)确定精子获能和精浆成分对TRPC通道功能和受精的影响。这些研究在两个方面是相关的。首先，它们可以促进我们对受精基本生物学的理解。其次，这些研究可能会对人类不孕症的治疗和新型避孕药具的设计产生治疗效果。特别是，精子中PIP2代谢物在响应透明带刺激时产生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.