Identification of an oocyte maturation hormone receptor

描述（由申请人提供）：在几乎所有的动物中，完全成熟的卵母细胞在减数分裂中保持一段时间，直到激素通过激活知之甚少的复杂信号转导途径打破这种停滞，最终恢复细胞周期。这一关键步骤赋予了卵母细胞对精子作出反应的能力。这个将被冻结的卵母细胞转化为能够受精的卵子的过程称为成熟。虽然卵母细胞成熟在所有动物物种中都是一个广泛保守的过程，并且一些关于调节成熟的激素的信息是已知的，但迄今为止，还没有在任何物种中明确地鉴定出卵母细胞成熟激素受体，这使得我们对这一基本事件的理解存在重大差距。本提案概述了一种新的策略，旨在识别一个简单的模型系统，即海星卵母细胞中的卵母细胞成熟激素受体。之所以选择海星作为模型系统，是因为已经确定了诱导成熟的激素1-甲基腺嘌呤（1-MA），并且知道信号通路是与g蛋白相关的，这将提供用于识别受体的信息。不同的基于同源性和功能性的克隆方法将用于串联努力鉴定编码1-MA受体的cDNA。鉴定和表征1-MA受体将使我们能够测试广泛接受的假设，即该受体是典型的g蛋白偶联受体（GPCR），并最终评估从卵母细胞表面激素到减数分裂恢复的信号通路。此外，该策略的成功应用将为其他物种（包括哺乳动物）成熟激素受体的研究提供概念证明。此外，除了该项目明显的生殖生物学方面，卵母细胞是一个很好的模型系统，可以理解基本的细胞信号传导事件。最后，癌症是由细胞的异常和不受调节的生长引起的，通常是由涉及gpcr的信号级联反应调节的。因此，本文提出的卵母细胞成熟研究可能会为细胞生长调节机制提供新的见解，并可能导致对癌症如何发展的更深层次的理解。

DESCRIPTION (provided by applicant): In nearly all animals, fully-grown oocytes remain arrested in meiosis for some time until hormones break this arrest by activating poorly understood, complex signal transduction pathways that culminate in the resumption of the cell cycle. This crucial step confers the capacity of the oocyte to respond to sperm. This process of converting the arrested oocyte into a fertilization competent egg is termed maturation. While oocyte maturation is a widely conserved process across all animal species, and some information is known about the hormones that regulate maturation, no oocyte maturation hormone receptor has been identified unambiguously in any species to date, defining a major gap in our understanding of this fundamental event. This proposal outlines a novel strategy designed to identify an oocyte maturation hormone receptor in a simple model system, the starfish oocyte. The starfish was chosen as the model system because the maturation-inducing hormone 1-methyladenine (1-MA) has been identified, and knowledge that the signaling pathway is G-protein linked provides information that will be used to identify the receptor. Distinct homology-based and functional cloning approaches will be used in a tandem effort to identify the cDNA encoding the 1-MA receptor. Identification and characterization of the 1-MA receptor will allow us to then test the widely-held hypothesis that this receptor is a canonical G-protein coupled receptor (GPCR) and eventually, to assess the signaling pathway leading from hormone at the oocyte surface to resumption of meiosis. Further, success using this strategy would provide proof of concept for investigations of the maturation hormone receptors of other species, including mammals. Further, beyond the obvious reproductive biology aspects of the project, oocytes are a good model system in which to understand basic cell signaling events. Finally, cancers result from an abnormal and unregulated growth of cells, which often is normally regulated by signaling cascades involving GPCRs. Therefore, the oocyte maturation studies proposed here potentially will provide new insights for the mechanisms of cell growth regulation and perhaps lead to a deeper understanding of how cancer develops.