Role of the EGF Network in Ovulation

EGF 网络在排卵中的作用

• 批准号: 7800954
• 负责人: Marco Conti
• 金额: $ 32.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800954
• 关键词: AREG gene; Ablation; Affect; Alleles; Amphiregulin; Biology; Cells; Data; EGFR inhibition; EREG gene; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epiregulin; Event; Family; Fertility; Follicular Fluid; Genes; Genetic; Goals; Gonadotropins; Growth Factor; Immunoprecipitation; In Vitro; Knock-out; Label; Laboratories; Late Effects; Ligands; Mediating; Meiosis; Metabolic; Metalloproteases; Molecular; Monitor; Mus; Mutation; Nuclear; Oocytes; Ovarian Follicle; Ovulation; Phenotype; Phosphorylation; Physiological; Physiology; Play; Process; Receptor Signaling; Regulation; Role; Signal Transduction; Testing; autocrine; base; betacellulin; design; granulosa cell; improved; in vitro Model; in vivo; inhibitor/antagonist; interest; member; mutant; oocyte maturation; ovulation time; paracrine; receptor; reproductive; research study; tumor

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.

描述（由申请人提供）：该提案的总体目标是了解 EGF 网络在 LH 诱导排卵过程中的功能。我们实验室的初步研究表明，EGF 样生长因子家族的三个成员（上皮调节蛋白/EREG、双调蛋白/AREG 和 betacellulin/BTC）在排卵时由 LH 诱导，并且将这些因子外源性应用于培养的卵泡概括了 LH 的多种影响，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 作用中发挥着不可或缺的作用。基于这些发现，我们提出这样的假设：EGF 网络的 LH 调节对于排卵过程至关重要。检验这一假设的研究分为三个具体目标。第一个具体目标是，我们将研究 EGF 网络的几个基因的消融对体内排卵过程的影响。将研究删除 AREG 或 EREG 基因以及影响配体和 EGF 受体的复合突变的小鼠的生殖表型。第二个具体目标是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调节。第三个具体目标将致力于了解 EGF 受体信号传导如何整合到促性腺激素在排卵期期间激活的信号传导级联中。这些研究将有助于我们了解排卵的生理学，这是一个对生育能力至关重要的过程。它们还将为设计操纵生育力或改善卵母细胞体外核和细胞质成熟的培养条件的药理学策略提供合理的基础。最后，更好地了解 EGF 样生长因子的功能将有助于了解一些妇科肿瘤的生物学特性。