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

• 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
• 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

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.

项目摘要/摘要 Neuregulin-1（NRG1）在Luteum（CL）生理学中的作用 功能性语料库（CL）的形成是生殖成功的绝对要求，并由 黄体激素（LH）的中期循环激增。 CL是一种瞬态卵巢内分泌结构，可保持怀孕 在前三个月的灵长类 孕酮（P4）。 CL缺陷有助于减少P4的产生，随后无法支持开发 胎儿和生殖失败。 CL生长和分化受生存和细胞死亡信号的严格调节， 包括内分泌（LH），伏植物内调节剂和细胞 - 细胞相互作用。 LH，P4和 在人类和动物模型中，炎症标记已得到很好的确立。用于维持怀孕，黄体 受精后，高度血管化CL的建立和开发，多种促炎和促进 需要凋亡因子来重塑排卵卵泡。而为了保护排卵的卵泡及其 周围的细胞/组织形成功能性CL需要大量的促生物和抗 针对促凋亡和促炎的微调和平衡机制的炎症因素 创造有利环境以维持CL差异化状态和阶段的因素。以前我们的实验室有 证明NRG1是表皮生长因子（EGF）家族的成员，是促性腺激素（卵泡刺激的 激素，FSH和LH）依赖于颗粒细胞（GCS）和theca细胞中的差异调节，并在该细胞中分泌 卵巢卵泡液（FF）作为细胞存活因子。其他实验室已经证明NRG1增强了两次凝集蛋白 （AREG）诱导的GC中的P4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 过早发展为中期II（MII）阶段，导致异常受精和生育。我们的初步 研究检测到大鼠黄体细胞（LCS）和CL中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LCS存活和抑制炎症细胞因子中起重要作用 和趋化因子分泌，并提出在LCS成熟和分化中可能起作用的作用，并且可以通过 自分泌和/或旁分泌机制。 NRG1及其基础的抗炎和生存功能 LCS和CL功能中的作用机理尚待定义。我们的长期目标是了解生理 NRG1在CL分化中的作用，通过获得对其抗炎和促生物效应的见解 机械细节。因此，在此提案中要检验的中心假设是NRG1是关键的细胞介体 LH刺激LC，支持Cl功能。