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: 7936600
• 负责人: SHUNICHI SHIMASAKI
• 金额: $ 8.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936600
• 关键词: Adenylate Cyclase; Affect; Age-Years; Aging; Animal Model; Applications Grants; 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; Oocytes; Ovarian; Ovarian hormone; Ovary; Ovulation; Pharmacologic Substance; Physiology; Play; Process; Production; Proteomics; Rattus; Research Project Grants; Role; Role Concepts; Signal Transduction; Site; System; Testing; Thinking; Treatment Protocols; Woman; age related; base; clinically relevant; desensitization; design; egg; feeding; granulosa cell; hormone sensitivity; human GRK6 protein; in vivo; innovation; mRNA Expression; novel; premature; prevent; public health relevance; 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）：在妇女中，卵巢储备中与年龄相关的减少最不利影响的功能降低了。这种与年龄相关的变化的基础是，显性卵泡无法释放可能经历正常胚胎发育的卵。目前的思想是，FSH动作的增加参与了36岁以后女性的繁殖力下降的机制。这项赠款代表了理解FSH动作机制的激动人心的进步。使用大鼠模型，我们最近发现，卵母细胞对于增强颗粒细胞的FSH作用至关重要。我们还发现，雌激素和卵母细胞的协同作用发生在FSH受体的下游和腺苷酸环化酶上游的位置。进一步的研究为颗粒细胞中存在的功能性G蛋白偶联受体激酶（GRK）/？ - 阻止蛋白系统提供了第一个证据。此外，我们证明，仅在卵母细胞的情况下，GRK-6才被雌激素有选择地抑制，这表明雌激素和卵母细胞通过防止GRK-6/？ - 抑制了GRK-6/？介导的生物学作用来协同增强FSH作用，包括通过Frestiviving protin-Activie protivie protins transdiuct的脱敏化的生物学作用。在此R21赠款提案中，我们将阐明卵母细胞在介导雌激素对颗粒细胞FSH敏感性的作用中起着强制性作用的分子机制。在AIM 1中，我们将检验我们的假设，即GRK-6/？ - 抑制蛋白系统与雌激素 - 元素共处的机制有关，从而增强了FSH作用。我们还将对卵巢grk/？ - 阻止素系统进行首次全面分析，该系统与FSH受体活性的介导有关。在AIM 2中，我们将在雌激素作用所需的卵母细胞和颗粒细胞之间剖析通信网络，并探索卵母细胞和颗粒细胞如何进行通信以刺激FSH作用。此外，我们将使用蛋白质组学和genechip确定在雌激素存在下在雌激素存在下在卵母细胞和颗粒细胞之间的通信网络中作用的因素。微阵列分析。拟议的项目应提供一个新颖的概念框架，以了解哺乳动物卵巢中雌激素作用的分子和细胞机制，通过将GRK/？ - 逮捕蛋白系统引入卵巢生理学，并可能导致发展卵巢功能障碍，尤其是衰老女性的药物治疗方案的突破。公共卫生相关性：刺激卵泡激素（FSH）是卵巢功能的重要激素，包括卵泡发育和排卵。我们最近发现，在存在卵母细胞但不是不存在的情况下，雌激素增强了卵泡细胞中的FSH作用。拟议的研究旨在阐明该发现的分子和细胞机制，这可能导致开发用于治疗卵巢功能障碍的药物治疗方案，尤其是在衰老的女性中。