Role of the EGF Network in Ovulation

描述(由申请人提供)：本提案的总体目标是了解EGF网络在促黄体生成素诱导排卵过程中的功能。我们实验室的初步研究表明，EGF样生长因子家族中的三个成员(表观调节蛋白/Ereg、两相调节蛋白/AREG和β细胞蛋白/BTC)是在排卵时被黄体生成素诱导的，外源应用于培养的卵泡可以概括黄体生成素的几种作用，包括卵母细胞恢复减数分裂和卵丘扩张。此外，药理学和初步遗传学研究表明，EGF受体信号在排卵中的促黄体生成素作用中起着不可或缺的作用。在这些发现的基础上，我们提出了假设，即促黄体生成素对EGF网络的调节在排卵过程中是关键的。检验这一假设的研究被组织成三个具体的目标。第一个特定的目的，我们将在体内研究EGF网络的几个基因的消融对排卵过程的影响。AREG或Ereg基因缺失以及影响配体和EGF受体的复合突变的小鼠将被研究生殖表型。对于第二个特定目标，将在颗粒细胞和完整卵泡的体外模型中研究EGF样生长因子的合成和加工及其分泌的调节。第三个具体目标将致力于了解EGF受体信号如何整合到促性腺激素在围排卵期激活的信号级联中。这些研究将有助于我们理解排卵的生理学，排卵是一个对生育至关重要的过程。它们还将为设计药物策略以控制受精性或改善卵母细胞体外核和细胞质成熟的培养条件提供合理的基础。最后，更好地了解EGF样生长因子的功能将有助于理解一些妇科感兴趣的肿瘤的生物学。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand the function of the EGF network during the LH-induced ovulatory process. Preliminary studies from our laboratory indicate that three members of the EGF-like growth factor family (epiregulin/EREG, amphiregulin/AREG, and betacellulin/BTC) are induced by LH at the time of ovulation and that exogenous application of these factors to cultured follicles recapitulates several effects of LH, including oocyte resumption of meiosis and cumulus expansion. In addition, an indispensable role of EGF receptor signaling in LH action during ovulation is suggested by pharmacological and preliminary genetic studies. On the basis of these findings, we propose the hypothesis that LH regulation of the EGF network is critical for the ovulatory process. Studies to test this hypothesis are organized into three specific aims. With the first specific aim, we will investigate the impact of ablation of several genes of the EGF network on the ovulatory process in vivo. Mice with deletion of the AREG or EREG gene and with compound mutations affecting a ligand and the EGF receptor will be studied for reproductive phenotypes. With the second specific aim, the synthesis and processing of EGF-like growth factors, as well as the regulation of their secretion, will be investigated in in vitro models of granulosa cells and intact follicles. The third specific aim will be devoted to understanding how EGF receptor signaling is integrated in the signaling cascades activated by gonadotropins during the periovulatory period. These studies will contribute to our understanding of the physiology of ovulation, a process critical for fertility. They will also provide the rational basis to design pharmacological strategies to manipulate fertility or to improve culture conditions for in vitro nuclear and cytoplasmic maturation of oocytes. Finally, a better understanding of the function of EGF-like growth factors will contribute to the understanding of the biology of some tumors of gynecological interest.