Role of mineralocorticoid receptor in primate ovarian function

盐皮质激素受体在灵长类动物卵巢功能中的作用

• 批准号: 7471142
• 负责人: CHARLES L CHAFFIN
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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/7471142
• 关键词: Aging; Agonist; American; Animal Model; Anovulation; Attenuated; Body of uterus; Bolus Infusion; CYP21A2 gene; Cell Nucleus; Centers for Disease Control and Prevention (U.S.); Contraceptive Agents; Contraceptive methods; Corpus Luteum Maintenance; Couples; Cytoplasm; Data; Deoxycorticosterone; Derivation procedure; Detection; Development; Estradiol; Feedback; Gene Targeting; Granulosa-Lutein Cells; Health; Human; Human Chorionic Gonadotropin; In Vitro; Infertility; Intervention; Knowledge; Laboratories; Link; Longevity; Luteal Phase; Luteinization; Luteolysis; Macaca; Macaca fascicularis; Macaca mulatta; Maintenance; Malignant neoplasm of ovary; Menopause; Menstrual cycle; Messenger RNA; Methods; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Morbidity - disease rate; Numbers; Oral; Outcome; Ovarian; Ovarian Hyperstimulation Syndrome; Ovarian Stimulations; Ovary; Pathology; Pathway interactions; Periodicity; Physiological; Physiology; Pilot Projects; Plague; Pregnancy loss; Primates; Process; Production; Progesterone; Proteins; Public Health; Reproduction; Research; Role; Signal Transduction; Source; Steroid 21-Monooxygenase; Steroids; Stimulus; System; Testing; Time; United States; Vision; Woman; Work; clinically significant; corpus luteum; granulosa cell; in vivo; mortality; nonhuman primate; novel; prevent; receptor; research study; species difference; stem; therapy development

DESCRIPTION (provided by applicant): The formation, function, and demise of the primate corpus luteum are critical aspects of menstrual cyclicity, infertility, and contraceptive intervention. Recent work by the applicant's laboratory has demonstrated the presence of an intra-ovarian mineralocorticoid system in the non-human primate. In rhesus monkeys undergoing controlled ovarian stimulation, an ovulatory stimulus increases the expression of 21-hydroxylase (CYP21A2) mRNA in a time-dependent manner. CYP21A2 converts progesterone to the potent mineralocorticoid receptor (MR) agonist 11-deoxycorticosterone (DOC), and thus correlates with the observation that the ovulatory hCG bolus increases intra-follicular levels of DOC. In order to verify an ovarian origin for DOC, granulosa cells were isolated prior to an ovulatory stimulus and cultured in the presence of hCG, resulting in a dramatic increase in media concentrations of DOC. MR is expressed in the cytoplasm of both luteinizing granulosa cells as well as the corpus luteum until the mid to mid-late luteal phase, at which time MR is translocated to the nucleus. Importantly, antagonism of MR during luteinization attenuates hCG-induced progesterone, indicating that cytoplasmic MR has a key role in luteinization of granulosa cells in vitro. This R21 application proposes to test the overall hypothesis that MR is critical during the lifespan of the corpus luteum with two specific aims using the non-human primate model. Specific aim 1 will determine if MR has a critical role in the development of the corpus luteum using an MR antagonist. It is expected that antagonism of MR in vivo will prevent the critical rise in progesterone, leading to anovulation and incomplete luteal formation. Specific aim 2 will test the hypothesis that MR promotes luteal function through progesterone synthesis, and that intra-luteal levels of DOC increase in parallel with progesterone. In both aims, specific gene targets of MR will be elucidated. These studies will be the first to demonstrate a key role for MR in the ovarian physiology of any species, and are expected to further our understanding of corpus luteum development, maintenance, and demise in a biomedically relevant primate model. PUBLIC HEALTH RELEVANCE: Pathologies associated with the ovary carry a high morbidity and mortality, largely through difficulty in detection, but also from a lack of treatment stemming from a rather incomplete understanding of basic ovarian processes. These include, for example, PCOS, ovarian cancer, and ovarian hyperstimulation syndrome (OHSS). In addition, infertility plagues a growing number of couples in the United States (>6 million; Center for Disease Control); a proportion of this infertility can be linked to insufficiency of P production during the luteal phase, although the underlying causes of this are completely unknown. Novel contraception remains a problem, with a large preponderance of North American women continuing to rely on derivations of combined oral contraception and no new methods in sight. Aging and reproduction is clearly a growing topic in the United States, and a better knowledge of basic ovarian processes will facilitate understanding the menopausal transition in women. These issues all support the idea that ovarian physiology is a relevant topic with profound health outcomes. Overall, these exploratory studies should reveal a novel signaling steroid pathway in the primate ovary that could have clinical significance for contraceptive development, infertility, and potentially ovarian cancer.

描述（由申请人提供）：灵长类动物语料库的形成，功能和消亡是月经循环，不育和避孕干预的关键方面。申请人实验室的最新工作表明，非人类灵长类动物中存在伏雄内矿物皮质激素系统。在受控卵巢刺激的恒河猴中，排卵刺激以时间依赖的方式增加了21-羟化酶（CYP21A2）mRNA的表达。 CYP21A2将孕酮转化为有效的矿物皮质激素受体（MR）激动剂11-脱氧核酮（DOC），因此与观察到的观察结果相关，即卵形HCG大推注会增加doc的流体内部水平。为了验证DOC的卵巢起源，在产卵刺激之前分离了颗粒细胞并在HCG存在下进行培养，从而导致DOC的培养基浓度急剧增加。 MR在黄体生成颗粒细胞的细胞质和叶黄素的细胞质中表达，直到中层中期的黄体期，此时MR迁移到细胞核。重要的是，黄体化过程中MR的拮抗作用减弱了HCG诱导的孕酮，表明细胞质MR在体外的颗粒细胞的黄体化中具有关键作用。该R21应用建议测试总体假设，即MR在Luteum的使用寿命中至关重要，使用非人类灵长类动物模型具有两个特定的目标。具体目标1将确定MR使用MR拮抗剂在Luteum的发展中是否具有关键作用。预计体内MR的拮抗作用将防止孕激素的临界升高，从而导致缺乏和不完全的黄体形成。具体目标2将检验MR通过孕激素合成促进黄体功能的假设，而白ey内的DOC水平与孕酮并行增加。在这两个目的中，将阐明MR的特定基因靶标。这些研究将是第一个在任何物种的卵巢生理学中都表现出MR的关键作用的研究，并有望进一步了解我们对叶黄素的发展，维持和消亡的理解。公共卫生相关性：与卵巢相关的病理具有很高的发病率和死亡率，这在很大程度上是由于难以检测而导致的，而且由于缺乏对基本卵巢过程的不完全理解而无法进行治疗。其中包括，例如PCOS，卵巢癌和卵巢过度刺激综合征（OHSS）。此外，不育会困扰着越来越多的夫妇（> 600万；疾病控制中心）；这种不孕症的一定比例与在黄体期间的P生产不足有关，尽管其根本原因是完全未知的。新颖的避孕仍然是一个问题，北美妇女的大量优势继续依赖于综合口服避孕的推导，看不到新的方法。在美国，衰老和繁殖显然是一个越来越多的话题，对基本卵巢过程的更好了解将有助于了解女性的更年期过渡。这些问题都支持这样一个观念，即卵巢生理学是一个相关的主题，具有深远的健康结果。总体而言，这些探索性研究应揭示灵长类动物卵巢中的新型信号传导类固醇途径，该途径可能对避孕性发育，不育和潜在的卵巢癌具有临床意义。