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LH诱导排卵过程中EGF网络的功能。我们实验室的初步研究表明，EGF样生长因子家族的三个成员（epiregulin/EREG，amphiregulin/AREG和betacellulin/BTC）在排卵时由LH诱导，这些因子对培养卵泡的外源性应用概括了LH的几种作用，包括卵母细胞减数分裂和卵丘扩张的恢复。此外，药理学和初步遗传学研究表明，EGF受体信号传导在排卵期间LH作用中发挥不可或缺的作用。基于这些发现，我们提出了一个假设，即LH调节EGF网络是排卵过程的关键。检验这一假设的研究分为三个具体目标。与第一个具体的目标，我们将研究的影响，消融的几个基因的EGF网络排卵过程中的体内。将研究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的生殖表型。第二个具体目标，EGF样生长因子的合成和加工，以及它们的分泌调节，将在颗粒细胞和完整卵泡的体外模型中研究。第三个具体的目标将致力于了解EGF受体信号是如何整合在促性腺激素激活的信号级联在围排卵期。这些研究将有助于我们了解排卵的生理学，这是生育的关键过程。它们也将为设计药理学策略以操纵生育力或改善卵母细胞体外核和胞质成熟的培养条件提供合理的基础。最后，更好地了解表皮生长因子样生长因子的功能将有助于了解一些妇科肿瘤的生物学。

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.