The role of reactive oxygen species (ROS) in the signaling of FSH and ovarian factors

虽然活性氧(ROS)的有害行为与人类卵巢病理有关，但令人惊讶的是，它们在卵巢生理中的作用尚不清楚。最近报道的ROS在排卵事件中的重要作用有力地支持了这种在啮齿动物中的作用。我们对体外受精来源的人颗粒细胞(GCs)的研究表明，当卵巢生长因子(如EGF)或儿茶酚胺作用于人GCs时，ROS就会产生。在这些研究过程中，我们观察到卵泡刺激素(FSH)，即控制卵泡发育的主要激素，也导致了人GCs中ROS的产生，所涉及的ROS被鉴定为H_2O_2。鉴于FSH在生殖医学中的基本重要性和广泛应用，我们计划探索FSH作用的这一未知部分，重点放在人类的情况上。我们的初步结果让我们怀疑NOX/DUOX家族的ROS产生酶和/或EGF受体反式激活参与了FSH作用的新方面。因此，我们将研究FSH如何导致H_2O_2的产生，H_2O_2如何在GC中作为细胞内信号因子发挥作用，以及它是否也可能是一个短程的细胞外信号分子。为此，计划进行一系列描述性和功能性研究。定位研究将追踪卵巢卵泡在卵泡发育过程中的NOX/DUOX-Forms/EGF受体。细胞和分子研究将研究FSH导致H_2O_2产生的信号通路以及这种ROS对GC的影响。FSH的ROS增强活性与其他卵巢因子之间的可能相互作用将通过实验和计算分析进行研究。我们期待我们的探索性项目将产生结果，这可能会让我们更好地了解一种关键荷尔蒙在雌性生殖中的作用。我们相信，我们的结果可能具有临床重要性。

While noxious actions of reactive oxygen species (ROS) are implicated in human ovarian pathology, their roles in ovarian physiology are surprisingly unknown. The recently documented essential involvement of ROS in ovulatory events strongly supports such a role in rodents. Our studies in IVF (in vitro fertilization)-derived human granulosa cells (GCs) showed that ROS are generated, when ovarian growth factors (e.g. EGF) or catecholamines act on human GCs. In course of these studies we made the observation that follicle stimulating hormone (FSH), i.e. the master hormone governing follicular development, also resulted in the generation of ROS in human GCs and the ROS involved was identified as H2O2. Given the fundamental importance and widespread use of FSH in reproductive medicine, we plan to explore this unknown part of FSH action with a focus on the human situation. Our preliminary results let us suspect involvement of the ROS generating enzymes of the NOX/DUOX family and/or of EGF receptor transactivation in the novel aspect of FSH action. Hence we will examine, how FSH leads to the generation of H2O2, how H2O2 acts as an intracellular signaling factor in GCs and whether it may also be a short-range extracellular signaling molecule. To this end a series of descriptive and functional studies are planned. Localization studies will trace NOX/DUOX-forms/EGF receptors in ovarian follicles during follicular development. Cellular and molecular studies will examine the signaling pathway of FSH that leads to H2O2 generation and the consequences of this ROS on GCs. Possible interactions between the ROS augmenting activities of FSH with other ovarian factors will be studied experimentally and by a computational analysis. We expect that our exploratory project will yield results, which may allow a better understanding of the actions of a crucial hormone in female reproduction. We believe that our results are of possible clinical importance.