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

虽然活性氧（ROS）的有害作用与人类卵巢病理学有关，但它们在卵巢生理学中的作用令人惊讶地未知。最近记录的ROS在排卵事件中的重要参与强烈支持啮齿动物中的这种作用。我们在体外受精（IVF）衍生的人颗粒细胞（GCs）中的研究表明，当卵巢生长因子（如EGF）或儿茶酚胺作用于人GCs时，会产生ROS。在这些研究过程中，我们观察到促卵泡激素（FSH），即控制卵泡发育的主激素，也导致人GC中ROS的产生，并且所涉及的ROS被鉴定为H2 O2。鉴于FSH在生殖医学中的重要性和广泛使用，我们计划探索FSH作用的这一未知部分，重点关注人类情况。我们的初步结果让我们怀疑参与的ROS生成酶的NOX/DUOX家族和/或EGF受体的反式激活的FSH行动的新方面。因此，我们将研究FSH如何导致H2 O2的产生，H2 O2如何在GC中作为细胞内信号传导因子，以及它是否也可能是一种短距离细胞外信号分子。为此，计划进行一系列描述性和功能性研究。定位研究将追踪卵泡发育过程中卵泡中的NOX/DUOX形式/EGF受体。细胞和分子研究将检查导致H2 O2产生的FSH信号通路以及这种ROS对GC的影响。FSH与其他卵巢因子的ROS增强活性之间可能的相互作用将通过实验和计算分析进行研究。 我们希望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女性生殖中一种关键激素的作用。我们相信我们的结果可能具有临床意义。

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.