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

Neuregulin-1 (NRG1) 在黄体 (CL) 生理学中的作用

基本信息

批准号：
10260383
负责人：
Indrajit Chowdhury
金额：
$ 35.5万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10260383
关键词：
Address Affect Amphiregulin Animal Model Anti-Inflammatory Agents Apoptotic Biochemical Biological Assay Blood Vessels Cell Communication Cell Death Signaling Process Cell Differentiation process Cell Maturation Cell Survival Cell physiology Cells Contraceptive methods Defect Development Differentiation Antigens Differentiation and Growth Endocrine Environment Epidermal Growth Factor Failure Family Female infertility Fertility Fertilization Fetal Development First Pregnancy Trimester Follicle Stimulating Hormone Follicular Fluid Future Goals Gonadotropins Infertility Inflammatory Investigation Knowledge Luteal Cells Luteal Phase Luteinizing Hormone MEKs Mediating Mediator of activation protein Meiosis Metaphase Molecular NRG1 gene Neuregulin 1 Oocytes Ovarian Ovary Pathway interactions Physiological Physiology Play Pregnancy Preventive Primates Production Progesterone Rattus Rodent Role Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Structure Supporting Cell Testing Therapeutic Tissues autocrine chemokine corpus luteum cytokine experimental study gain of function granulosa cell human model immunocytochemistry inflammatory marker insight intraovarian loss of function member molecular diagnostics novel paracrine population based preclinical study pregnant premature prevent receptor reproductive reproductive success response steroid hormone theca cell tool

项目摘要

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.

项目概要/摘要 Neuregulin-1 (NRG1) 在黄体 (CL) 生理学中的作用功能性黄体 (CL) 的形成是生殖成功的绝对要求，并且是由黄体生成素 (LH) 的周期中期激增。 CL是维持妊娠的短暂性卵巢内分泌结构灵长类动物在妊娠前三个月和啮齿类动物在整个怀孕期间通过类固醇激素的产生黄体酮 (P4)。 CL 缺陷导致 P4 产量减少，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间相互作用。 LH、P4 和炎症标记物已在人类和动物模型中得到很好的建立。维持妊娠、黄体受精后高度血管化的 CL 的建立和发展，大量的促炎和促排卵卵泡的组织重塑需要凋亡因子。然而，为了保护排卵卵泡及其周围细胞/组织形成功能性 CL 需要大量的促生存和抗- 炎症因子微调和平衡促凋亡和促炎症机制因素创造了良好的环境，使CL保持差异化的状态和阶段。之前我们实验室有证明 NRG1 是表皮生长因子 (EGF) 家族的成员，是促性腺激素（卵泡刺激素）激素（FSH 和 LH）依赖于颗粒细胞 (GC) 和卵泡膜细胞的差异调节，并分泌于卵巢卵泡液（FF）作为细胞生存因子。其他实验室已证明 NRG1 可以增强双调蛋白 (AREG) 诱导 GC 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，并防止过早进展到中期 II (MII) 阶段，导致受精和生育力异常。我们的初步研究在大鼠黄体细胞 (LC) 和 CL 中检测到 NRG1 的 LH 依赖性表达。此外，我们的初步研究还提供了新的证据表明 NRG1 在 LC 存活和炎症细胞因子抑制中发挥重要作用和趋化因子分泌，并表明在 LC 成熟和分化中可能发挥作用，并且可能通过自分泌和/或旁分泌机制。 NRG1的抗炎和促生存功能及其基础 LC 和 CL 功能的作用机制尚未确定。我们的长期目标是了解生理学通过深入了解 NRG1 在 CL 分化中的作用，了解其抗炎和促生存作用机械细节。因此，本提案要测试的中心假设是 NRG1 是一种关键的细胞介质 LH 刺激 LC，支持 CL 功能。