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

项目概要/摘要 Neuregulin-1（NRG 1）在黄体（CL）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，并由 黄体生成素（LH）的周期中期激增。CL是维持妊娠的短暂卵巢内分泌结构 在灵长类动物的头三个月和啮齿类动物的整个怀孕期间，通过产生类固醇激素 孕酮（P4）。CL缺陷导致P4产量减少，随后无法支持开发 胎儿和生殖失败。CL生长和分化受到存活和细胞死亡信号的严格调节， 包括内分泌（LH）、卵巢内调节因子和细胞间相互作用。LH、P4和 炎症标志物已经在人和动物模型中得到很好的建立。用于维持妊娠，黄体 受精后高度血管化CL的建立和发展，过多的促炎和促炎因子， 凋亡因子是排卵卵泡组织重塑所必需的。而为了保护排卵卵泡及其 用于形成功能性CL的周围细胞/组织需要过多的促存活和抗- 调节和平衡促凋亡和促炎机制 创造有利环境维持CL分化状态和阶段的因素。此前，我们的实验室 NRG 1是表皮生长因子（EGF）家族的成员，具有促性腺激素（卵泡刺激素 激素，FSH和LH）依赖性差异调节颗粒细胞（GC）和卵泡膜细胞，并分泌在 卵巢卵泡液（FF）作为细胞存活因子。其他实验室已经证明NRG 1可以增强双调蛋白 （AREG）诱导的GCs中P4的产生，并在卵母细胞减数分裂成熟中发挥重要的调节作用， 过早进展到中期II（MII）阶段，导致异常受精和生育力。我们的初步 研究检测到NRG 1在大鼠黄体细胞（LC）和CL中的LH依赖性表达。此外，我们的初步研究 也提供了新的证据表明NRG 1在LC存活和抑制炎性细胞因子中起重要作用 和趋化因子分泌，并建议在LC成熟和分化的可能作用，并可能通过一个 自分泌和/或旁分泌机制。NRG 1的抗炎和促生存功能及其机制 LC和CL功能中的作用机制尚待定义。我们的长期目标是了解 通过深入了解NRG 1在CL分化中的抗炎和促生存作用， 机械细节因此，在这个提议中要测试的中心假设是NRG 1是一个关键的细胞介质 LH刺激LC，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.