A Novel Function of the Oocyte in Estrogen-Regulated FSH Action

卵母细胞在雌激素调节 FSH 作用中的新功能

• 批准号: 7470511
• 负责人: SHUNICHI SHIMASAKI
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470511
• 关键词: Adenylate Cyclase; Affect; Age; Age-Years; Aging; Animal Model; Applications Grants; Arrestin; Arrestins; Biological; Cells; Communication; Complex; Data; Development; Down-Regulation; Embryonic Development; Estradiol; Estrogens; Failure; Fertility; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Functional disorder; G protein coupled receptor kinase; GTP-Binding Proteins; Grant; Growth and Development function; Lead; Mediating; Mediation; Mitogen-Activated Protein Kinases; Modeling; Molecular; Nature; Numbers; Oocytes; Ovarian; Ovarian hormone; Ovary; Ovulation; Pharmacologic Substance; Physiology; Play; Process; Production; Proteomics; Public Health; Rattus; Research Project Grants; Role; Role Concepts; Signal Transduction; Site; System; Testing; Thinking; Treatment Protocols; Woman; age related; base; clinically relevant; concept; desensitization; design; egg; feeding; granulosa cell; hormone sensitivity; human GRK6 protein; in vivo; innovation; mRNA Expression; novel; prevent; research study; synergism

DESCRIPTION (provided by applicant): In women, one function most adversely affected by the age-related decrease in ovary reserve is decreased fecundity. The basis for this age-related change is the failure of dominant follicles to release eggs that can undergo normal embryonic development. The current thinking is that increased FSH action is involved in the mechanisms underlying decreased fecundity in women after 36 years of age. This grant represents an exciting advance in understanding the mechanisms of FSH action. Using the rat model, we have recently discovered that the oocyte is essential for estrogen activity in enhancing FSH action in granulosa cells. We have also found that the synergistic action of estrogen and oocytes occurs at a site downstream of the FSH receptor and upstream of adenylate cyclase. Further studies have provided the first evidence for a functional G protein-coupled receptor kinase (GRK)/?-arrestin system present in granulosa cells. Moreover, we demonstrate that GRK-6 is selectively suppressed by estrogen only in the presence of oocytes, suggesting that estrogen and oocytes synergistically enhance FSH action by preventing GRK-6/?-arrestin-mediated biological actions including desensitization of G protein signaling and activation of mitogen-activated protein kinase signal transduction induced by FSH. In this R21 grant proposal, we will elucidate the molecular mechanisms by which the oocyte plays an obligatory role in mediating estrogen action on the FSH sensitivity of granulosa cells. In Aim 1, we will test our hypothesis that the GRK-6/?-arrestin system is involved in the mechanism by which estrogen-oocyte co-treatment enhances FSH action. We will also provide the first comprehensive analysis of the ovarian GRK/?-arrestin system, which has been implicated in the mediation of the FSH receptor activity. In Aim 2, we will dissect the communication network between the oocyte and granulosa cell that is required for estrogen action and explore how oocytes and granulosa cells communicate in order for estrogen to stimulate FSH action. Moreover, we will identify the factor(s) that acts in the communication network between oocytes and granulosa cells to augment FSH action in the presence of estrogen, using proteomics and GeneChip. microarray analyses. The proposed project should provide a novel conceptual framework for understanding the molecular and cellular mechanisms of estrogen action in mammalian ovaries by introducing the GRK/?-arrestin system into the ovarian physiology and may lead a breakthrough in developing pharmacological regimens for treating ovarian dysfunctions, particularly in aging women. PUBLIC HEALTH RELEVANCE: Follicle-stimulating hormone (FSH) is an essential hormone for the ovarian function that includes follicle development and ovulation. We have recently discovered that estrogen enhances FSH action in follicular cells in the presence, but not absence, of oocytes. The proposed studies aim to elucidate the molecular and cellular mechanisms of this finding, which may lead to develop pharmaceutical regimens for treating ovarian dysfunctions, particularly in aging women.

描述（由申请人提供）：在女性中，受年龄相关的卵巢储备功能下降影响最大的一项功能是生育力下降。这种与年龄相关的变化的基础是优势卵泡无法释放能够进行正常胚胎发育的卵子。目前的观点是，FSH 作用增加与 36 岁后女性生育力下降的机制有关。这笔资助代表了对 FSH 作用机制的理解取得了令人兴奋的进展。利用大鼠模型，我们最近发现卵母细胞对于增强颗粒细胞中 FSH 作用的雌激素活性至关重要。我们还发现雌激素和卵母细胞的协同作用发生在FSH受体下游和腺苷酸环化酶上游的位点。进一步的研究为颗粒细胞中存在功能性 G 蛋白偶联受体激酶 (GRK)/β-抑制蛋白系统提供了第一个证据。此外，我们证明GRK-6仅在卵母细胞存在的情况下才被雌激素选择性抑制，这表明雌激素和卵母细胞通过阻止GRK-6/β-抑制蛋白介导的生物作用（包括G蛋白信号脱敏和FSH诱导的丝裂原激活蛋白激酶信号转导的激活）协同增强FSH作用。在这项 R21 资助提案中，我们将阐明卵母细胞在介导雌激素对颗粒细胞 FSH 敏感性的作用中发挥重要作用的分子机制。在目标 1 中，我们将检验我们的假设，即 GRK-6/β-arrestin 系统参与雌激素-卵母细胞共同治疗增强 FSH 作用的机制。我们还将首次对卵巢 GRK/β-arrestin 系统进行全面分析，该系统与 FSH 受体活性的介导有关。在目标 2 中，我们将剖析雌激素作用所需的卵母细胞和颗粒细胞之间的通信网络，并探讨卵母细胞和颗粒细胞如何通信以便雌激素刺激 FSH 作用。此外，我们将使用蛋白质组学和基因芯片来确定在卵母细胞和颗粒细胞之间的通信网络中起作用的因子，以在雌激素存在的情况下增强 FSH 作用。微阵列分析。该项目应通过将GRK/β-arrestin系统引入卵巢生理学，为理解哺乳动物卵巢中雌激素作用的分子和细胞机制提供一个新颖的概念框架，并可能在开发治疗卵巢功能障碍（特别是老年女性）的药物治疗方案方面取得突破。公众健康相关性：卵泡刺激素 (FSH) 是卵巢功能（包括卵泡发育和排卵）的必需激素。我们最近发现，在卵母细胞存在但不存在的情况下，雌激素会增强卵泡细胞中 FSH 的作用。拟议的研究旨在阐明这一发现的分子和细胞机制，这可能导致开发治疗卵巢功能障碍的药物方案，特别是老年女性的卵巢功能障碍。