Identification of an oocyte maturation hormone receptor

描述（由申请人提供）：在几乎所有动物中，完全生长的卵母细胞在减数分裂中保持停滞一段时间，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。这一关键步骤赋予卵母细胞对精子做出反应的能力。这种将停滞的卵母细胞转化为具有受精能力的卵子的过程称为成熟。虽然卵母细胞成熟是所有动物物种中广泛保守的过程，并且关于调节成熟的激素的一些信息是已知的，但迄今为止在任何物种中都没有明确鉴定出卵母细胞成熟激素受体，这在我们对这一基本事件的理解中定义了一个主要空白。该建议概述了一种新的策略，旨在确定一个简单的模型系统，海星卵母细胞的卵母细胞成熟激素受体。海星被选为模型系统，因为成熟诱导激素1-甲基腺嘌呤（1-MA）已被确定，并知道信号通路是G蛋白连接提供的信息，将用于识别受体。不同的同源性为基础的和功能性克隆的方法将被用于一个串联的努力，以确定编码1-MA受体的cDNA。1-MA受体的鉴定和表征将使我们能够测试广泛持有的假设，即该受体是典型的G蛋白偶联受体（GPCR），并最终评估导致从卵母细胞表面激素到减数分裂恢复的信号通路。此外，使用这种策略的成功将为其他物种（包括哺乳动物）的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，在其中了解基本的细胞信号事件。最后，癌症是由细胞的异常和不受调节的生长引起的，而细胞的生长通常受到涉及GPCR的信号级联的调节。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入了解。

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.