The role of Neuregulin-1 (NRG1) in corpus luteum (CL) physiology

项目摘要/摘要 神经调节蛋白-1(NRG1)在黄体生理中的作用 功能性黄体(CL)的形成是生殖成功的绝对要求，由 黄体生成素(LH)周期中期激增。CL是维持妊娠的一过性卵巢内分泌结构 在灵长类动物中，在怀孕前三个月，在啮齿动物中，在整个怀孕期间通过类固醇激素的产生 黄体酮(P4)。CL缺陷会导致P4产量下降，并随后无法支持发育中的 胎儿和生殖障碍。CL的生长和分化受到生存和细胞死亡信号的严格调控， 包括内分泌(LH)、卵巢内调节因子和细胞-细胞间相互作用。黄体生成素、孕酮和黄体生成素之间的相互作用 炎症标志物已经在人类和动物模型中得到了很好的证实。用于维持妊娠、黄体 受精后高度血管化的CL的建立和发展--过量的促炎和促炎因子 细胞凋亡因子是排卵卵泡组织重塑所必需的。然而，为了保护排卵的卵泡及其 形成功能性CL所需的周围细胞/组织需要过多的促生存和抗 炎症因子微调和平衡促细胞凋亡和促炎机制 营造良好的环境，保持CL分化的状态和阶段。此前，我们的实验室已经 NRG1是表皮生长因子(EGF)家族的一员，是促性腺激素(卵泡刺激素)的成员 激素、卵泡刺激素和促黄体生成素)在颗粒细胞(GC)和卵泡膜细胞(TECs)中差异调节，并在 卵泡液(FF)作为细胞存活因子。其他实验室已经证明，NRG1增强了两亲调节蛋白 AREG诱导GCs产生P4，并在卵母细胞减数分裂成熟过程中发挥重要的调节作用，并防止 过早进展到中期II(MII)阶段，导致异常受精和生育。我们的预赛 研究发现大鼠黄体细胞(LCS)和黄体细胞(CL)中NRG1的表达依赖于黄体生成素。此外，我们的初步研究 也提供了新的证据，证明NRG1在LCS存活和抑制炎性细胞因子方面发挥重要作用 和趋化因子的分泌，提示在LC的成熟和分化中可能起作用，并可能通过 自分泌和/或旁分泌机制。NRG1的抗炎和促生存功能及其基础 LCS和CL功能的作用机制尚未明确。我们的长期目标是了解生理学 NRG1通过了解其抗炎和促存活作用在CL分化中的作用 机械化的细节。因此，在这项提议中要检验的中心假设是NRG1是一个关键的细胞介体 促黄体生成素刺激LCS，支持CL功能。

PROJECT SUMMARY/ABSTRACT The role of Neuregulin-1 (NRG1) in corpus luteum (CL) physiology Formation of a functional corpus luteum (CL) is an absolute requirement for reproductive success and is induced by the mid-cycle surge of luteinizing hormone (LH). The CL is a transient ovarian endocrine structure that maintains pregnancy in primate during the first trimester and in rodents during the entire pregnancy by the production of steroid hormone progesterone (P4). CL defects contribute to decreasing P4 production and subsequent inability to support a developing fetus and reproductive failures. CL growth and differentiation are tightly regulated by both survival and cell death signals, including endocrine (LH), intra-ovarian regulators and cell-cell interactions. The interplay between the LH, P4 and inflammatory markers have been well established in human and animal models. For maintaining pregnancy, luteal establishment and development of highly vascularized CL upon fertilization, a plethora of pro-inflammatory and pro- apoptotic factors are needed for tissue remodeling of the ovulated follicle. Whereas, to protect ovulated follicle and its surrounding cells/tissues for the formation of a functional CL requires a plethora of pro-survival and anti- inflammatory factors to fine-tune and counterbalance mechanism against pro-apoptotic and pro-inflammatory factors to create a favorable environment to maintain CL differentiated state and stage. Previously our lab has demonstrated that NRG1, a member of epidermal growth factor (EGF) family, is gonadotropin (follicle stimulating hormone, FSH and LH) dependent differentially regulated in granulosa cells (GCs) and theca cells, and secreted in the ovarian follicular fluid (FF) as a cellular survival factor. Other labs have demonstrated that NRG1 enhances amphiregulin (AREG)-induced P4 production in GCs, and exerts an important regulatory role in oocyte meiotic maturation, and prevent premature progression to the metaphase II (MII) stage that leads to abnormal fertilization and fertility. Our preliminary studies detected LH dependent expression of NRG1 in rat luteal cells (LCs) and CL. Furthermore, our preliminary studies also provided novel evidence that NRG1 plays an important role in LCs survival and inhibition of inflammatory cytokines and chemokine secretion, and suggest a possible role in LCs maturation and differentiation, and, may act through an autocrine and/or paracrine mechanism. The anti-inflammatory and pro-survival functions of NRG1 and its underlying mechanism of action in LCs and CL functions are yet to be defined. Our long-term goal is to understand the physiological role of NRG1 on CL differentiation through obtaining insights into its anti-inflammatory and pro-survival effect in mechanistic detail. Thus, the central hypothesis to be tested in this proposal is that NRG1 is a critical cellular mediator of LH stimulation of LCs, which supports CL function.