Neuregulin-1 (NRG1) in preovulatory granulosa cell survival and anti-inflammatory role

 描述(由申请人提供)：尽管进行了大量的流行病学和临床研究，但卵巢功能障碍的起始和发展轨迹仍不清楚。排卵是将成熟的卵母细胞和周围的卵丘细胞从卵巢表面释放出来的独特生物过程。黄体生成素(LH)诱导的排卵类似于炎症反应。促黄体生成素、卵巢类固醇激素和炎症标志物之间的关系已经在人类和动物模型中得到很好的证实(1)。虽然过多的促炎因子在卵泡破裂过程中是必不可少的，但为了保护其周围的细胞/组织，排卵需要多种抗炎和细胞保护或生存因子，包括EGF家族成员、细胞因子、基质因子。我们的初步研究在大鼠排卵前颗粒细胞(PO-GC)、排卵前卵泡液(FF)和黄体(CL)中检测到表皮生长因子(EGF)家族成员神经调节蛋白-1(NRG1)。我们的结果还提供了新的证据，表明NRG1在PO-GC存活和抑制炎性细胞因子分泌方面发挥重要作用，并可能参与颗粒细胞的分化和排卵前卵泡的抗炎因子，并可能通过自分泌和/或旁分泌方式发挥作用。此外，已知NRG1具有神经保护和抗炎特性，以及心血管功能(2，3)。然而，NRG1在排卵前卵泡的GCs中的抗炎和促存活功能及其潜在的作用机制尚不清楚。了解NRG1在调控PO-GC功能时所使用的细胞内信号通路可能有助于确定克服卵巢功能障碍的策略。基于我们的初步研究和文献，该应用的目的是从机制细节上揭示NRG1的抗炎和促生存作用。因此，在这项建议中要检验的中心假设是，NRG1是促黄体生成素刺激PO-GC的关键细胞内介质，支持排卵前卵泡成熟。

 DESCRIPTION (provided by applicant): Despite considerable epidemiological and clinical research, the initiation and trajectory of ovarian dysfunction remain unclear. Ovulation is the unique biological process by which a mature oocyte and surrounding cumulus cells are released from the surface of the ovary. Luteinizing hormone (LH)-induced ovulation is similar to an inflammatory response. Relationships between the LH, ovarian steroid hormones and inflammatory markers have been well established in human and animal models (1). While plethora of pro-inflammatory factors are essential for the process of follicle rupture, whereas to protect its surrounding cells/tissues, ovulation requires multiple anti-inflammatory and cellular protective or survival factors including EGF-family members, cytokines, matrix factors. Our preliminary studies detected the epidermal growth factor (EGF) family member, neuregulin- 1 (NRG1) in rat pre-ovulatory granulosa cells (PO-GC), preovulatory follicular fluid (FF) and corpus lutea (CL). Our results also provided novel evidence that NRG1 plays an important role in PO-GC survival and inhibition of inflammatory cytokines secretion, and suggest a possible role in granulosa cells (GCs) differentiation and an anti-inflammatory factor in pre-ovulatory follicle and may act through autocrine and/or paracrine manner. Furthermore, NRG1 is known to have neuroprotective and anti-inflammatory properties, and cardiovascular functions (2,3). However, the anti-inflammatory and pro-survival function of NRG1 and its underlying mechanism of action in GCs of pre-ovulatory follicles are yet to be defined. Understanding the intracellular signaling pathways utilized by the NRG1 in governing PO-GC functions are likely to help identify strategies to overcome ovarian dysfunction. Based on our preliminary studies and on the literature, the goal of this application is to unravel the anti-inflammatory and pro-surviva role of NRG1 in mechanistic detail. Thus, the central hypothesis to be tested in this proposal is that NRG1 is critical intracellular mediators of LH stimulation of PO-GCs, which supports preovulatory follicular maturation.