Physiological Mechanisms Underlying Heightened Responsiveness of Gonadotropes to

促性腺激素反应增强的生理机制

• 批准号: 8281320
• 负责人: Colin M Clay
• 金额: $ 29.04万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281320
• 关键词: Agonist; Anterior Pituitary Gland; Binding; Biological; Blood Circulation; Carcinoma; Cell Line; Cell membrane; Cells; Clinical; Competence; Contraceptive methods; Cues; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Development; Disease; Endocrine Glands; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrogens; Event; Fertility; Fibroid Tumor; Generations; Genes; Genetic Transcription; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Health; Hypothalamic structure; Luteinizing Hormone; Mediating; Membrane; Mus; Neurons; Neuropeptides; Ovulation; Pathway interactions; Peripheral; Pharmacologic Substance; Phenotype; Physiological; Pituitary Gland; Receptor Gene; Regulation; Regulatory Element; Reproduction; Reproductive Endocrinology; Research; Sheep; Signal Transduction; Site; Testing; Tissues; Transgenic Mice; Uterine Fibroids; Vertebrates; Work; endometriosis; in vitro Model; in vitro testing; in vivo; mouse model; novel; promoter; public health relevance; receptor; receptor expression; reproductive; reproductive hormone; response

DESCRIPTION (provided by applicant): Ovulation is one of the most fundamental events in reproduction and requires a dramatic surge of luteinizing hormone (LH) released by the anterior pituitary gland into the peripheral circulation. The secretion of LH from the pituitary is cued by the hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH). Thus, the secretion of GnRH from hypothalamic neurons and its interpretation by gonadotropes in the pituitary constitute the essential central events for reproductive competence. Thus, understanding and, ultimately, controlling the mechanisms underlying the generation of the preovulatory LH surge remains a primary focus of research in reproductive endocrinology at both the basic and clinical levels. It has become almost axiomatic that estradiol- 172 (E2) secreted from the preovulatory follicle serves as the most proximate regulator of the LH surge via two sites of action. First, E2 enhances sensitivity of the pituitary by increasing GnRH receptor expression. Second and temporally delayed, it stimulates increased hypothalamic secretion of GnRH. As these 2 physiological sequelae to elevated E2 have been known for decades, it is troubling that our understanding of the underlying mechanisms at both the level of GnRH secretion (hypothalamic) and GnRH responsiveness (pituitary) remains quite undeveloped. In regard to the latter, the lack of progress reflects the inability of in vitro models (cell lines) and promoters (mouse GnRH receptor gene) to recapitulate the increase in pituitary responsiveness to GnRH induced by E2. In contrast, using transgenic mouse models we have demonstrated that the proximal promoter of the ovine GnRH receptor gene is highly E2 responsive. This E2 responsive phenotype does not; however, appear to involve direct binding of activated estrogen receptor (ER) to the sheep gene. Rather, we find that membrane impermeable conjugates of E2 regulate LH secretion in sheep and increase GnRH receptor expression. As such, heightened responsiveness of the pituitary preceding the preovulatory LH surge may reflect E2 signaling through a membrane site of action - this is the central biological issue that exists as the core of our proposed research. Accordingly, using both in vivo and in vitro tests of promoter function and parallel analyses of the endogenous ovine GnRH receptor gene we will determine the hierarchy of ER subtypes that underlie E2 responsiveness of GnRH receptor expression, the initial cellular site of action of E2 that elicits enhanced expression of GnRH receptors and the identity of the regulatory element(s) that mediate the transcriptional response of the GnRHR gene to E2. Understanding regulation of GnRH and its receptor is important for fertility control; however, GnRH agonists and antagonists are used to treat fibroid tumors, endometriosis, and reproductive tissue carcinomas thus underscoring the need for a full understanding of GnRH and the GnRH receptor in both health and disease. PUBLIC HEALTH RELEVANCE: These studies will refine our understanding of estrogen signaling in the anterior pituitary gland (the "master" endocrine gland) as well novel mechanisms underlying estrogen regulation of important physiological targets throughout the body. Understanding these mechanisms is critical to the development of new generations of both pro and anti-estrogen-like pharmaceuticals that are increasingly specific for the desired biological effect. Understanding physiological regulation of reproductive hormones like gonadotropin releasing hormone (GnRH) and the GnRH receptor is important to fertility regulation; however, the application of potent GnRH agonists and antagonists in the treatment of uterine fibroids, endometriosis and reproductive tissue carcinomas underscores the importance of this topic in both health and disease.

描述（由申请人提供）：排卵是繁殖中最基本的事件之一，需要垂体前腺释放到外围循环中的叶酸激素（LH）急剧激增。 LH从垂体中的分泌是由下丘脑神经肽，促性腺激素释放激素（GNRH）提出的。因此，在垂体中，gnRH的分泌及其在垂体中的促性腺激素的解释构成了生殖能力的基本核心事件。因此，理解并最终控制了产生前LH激增的基础机制仍然是基本和临床水平上生殖内分泌学研究的主要重点。通过两个作用部位，雌二醇-172（E2）分泌的雌二醇172（E2）几乎是公理的。首先，E2通过增加GnRH受体表达来增强垂体的敏感性。第二和时间延迟，它刺激了GNRH下丘脑分泌的增加。由于这两种生理后遗症已经闻名了E2数十年，因此我们对GNRH分泌水平（下丘脑）和GNRH反应性（垂体）的理解是我们对基本机制的理解令人不安的。关于后者，缺乏进展反映了体外模型（细胞系）和启动子（小鼠GNRH受体基因）的无能，以概括E2诱导的垂体反应性对GNRH的增加。相反，使用转基因小鼠模型，我们证明了卵子GnRH受体基因的近端启动子具有高度E2的响应性。 E2反应型表型没有；但是，似乎涉及活化的雌激素受体（ER）与绵羊基因的直接结合。相反，我们发现E2的膜不渗透结合物调节绵羊中的LH分泌并增加GnRH受体表达。因此，在排卵前LH激增之前的垂体的反应性提高可能反映了通过膜的作用部位的E2信号传导 - 这是我们提出的研究的核心存在的核心生物学问题。因此，使用体内和体外测试的启动子功能和内源性卵子GNRH受体基因的平行分析，我们将确定E2亚型的层次结构，这些e2 e2 e2 e2 e2受体表达的反应性，E2的初始细胞位点E2的初始细胞位点，使gnrh受体表达均增强了gnrh受体的表达，以至于均具有差异性的表达。 GnRHR基因至E2。了解GNRH及其受体的调节对于生育能力控制很重要。然而，GNRH激动剂和拮抗剂用于治疗肌瘤肿瘤，子宫内膜异位症和生殖组织癌，因此强调了健康和疾病中对GNRH和GNRH受体充分了解的必要性。 公共卫生相关性：这些研究将完善我们对垂体前腺体中雌激素信号传导的理解（“主”内分泌腺体），以及整个体内重要生理靶标的雌激素调节的新型机制。了解这些机制对于越来越多地针对所需的生物学作用的新一代和抗雌激素样药物的新一代至关重要。了解生殖激素（如促性激素释放激素（GNRH）和GNRH受体）的生理调节对生育能力调节很重要。然而，有效的GnRH激动剂和拮抗剂在子宫肌瘤，子宫内膜异位症和生殖组织癌中的治疗中的应用强调了该主题在健康和疾病中的重要性。