Endothelin-2 in Ovarian Follicle Rupture

卵巢卵泡破裂中的内皮素 2

• 批准号: 7572871
• 负责人: CHEMYONG JAY KO
• 金额: $ 23.14万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7572871
• 关键词: Animal Model; Binding Sites; Biochemical; Biochemical Process; Clinical; Cyst; Databases; Development; Disease; Endothelin; Endothelin Receptor; Endothelin Receptor Antagonist; Endothelin-2; Estrogen Receptor alpha; Estrogens; Experimental Models; Failure; Female infertility; Gene Expression; Gene Expression Profiling; Genes; Goals; Growth; Hormonal; Immunohistochemistry; In Situ Hybridization; Individual; Indomethacin; Infertility; Injection of therapeutic agent; Isometric Exercise; Knockout Mice; Knowledge; Label; Lead; Link; Luteinizing Hormone; Mammalian Oviducts; Measurement; Measures; Mediating; Molecular; Molecular Profiling; Mus; Oocytes; Ovarian; Ovarian Diseases; Ovarian Follicle; Ovarian Tissue; Ovary; Ovulation; PTGS2 gene; Pattern; Pituitary Gonadotropins; Porifera; Process; Progesterone; Progesterone Receptors; Prostaglandins; RU-486; Radioimmunoassay; Rattus; Research Personnel; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Role; Rupture; Smooth Muscle; Symptoms; Syndrome; System; Techniques; Theca Externa; Tissues; Vasoactive Intestinal Peptide; constriction; corpus luteum; genome-wide; granulosa cell; in vivo; inhibitor/antagonist; intraovarian; muscular structure; muscular system; novel; programs; receptor; research study; tezosentan; therapeutic development; therapeutic target

The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in follicle rupture. The program of ovulation is activated by a surge of luteinizing hormone, which initiates dramatic changes in molecular, biochemical, and physical aspects of the ovary, eventually leading to rupture of follicles. However, the factors involved in and the mechanism governing the process of follicle rupture are yet to be unveiled. Using a gene expression profiling approach, we have identified EDN-2, a potent smooth muscle constrictor, which is exclusively and transiently expressed in the granulosa cells of periovulatory follicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in the ovarian tissue, while tezosentan, an endothelin receptor antagonist, released the contraction. These novel findings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture of the follicle. Supporting the hypothesis, immunohistochemical analysis identified a well-organized smooth muscle layer in the theca externa of each follicle, which forms a sponge-like smooth muscle network at the whole ovarian level. Furthermore, we found that intraovarian injection of tezosentan prior to ovulation completely blocked follicle rupture. In this study, we will elucidate the mechanism of EDN-2 action in follicle rupture. We will determine the target tissues of EDN-2 action, the endothelin receptor subtype(s) that mediates EDN-2 action, and the ovarian concentration of EDN-2. We will also determine the mechanism of endothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrice molecules (VIPs, PACAPs, and prostaglandins). In addition, the functional link of progesterone, estrogen, and prostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposal is in the identification of EDN-2 and the ovarian smooth muscle network as the key components of follicle rupture. The novelty of the proposed experiments is the interdisplinary approachs (genome-wide gene expression profiling, intraovarian injection, and isometric tension measurement). The proposed studies are exceptionally important in order to further our understanding of the mechanism of follicle rupture. The proposed experiments will provide clinical direction in identifying the therapeutic target for the cure of annovulatory symptoms, one of the leading causes of female infertility.

本研究旨在阐明内皮素-2（EDN-2）在卵泡中的作用机制 破裂排卵程序是由促黄体激素的激增激活的， 卵巢的分子、生物化学和物理方面的变化，最终导致卵巢破裂。 毛囊然而，卵泡破裂过程中涉及的因素和机制尚不清楚。 即将揭晓使用基因表达谱的方法，我们已经确定了EDN-2，一个有效的平滑 肌肉收缩，这是专门和短暂表达的颗粒细胞排卵周 排卵前的卵泡。我们发现，EDN-2诱导快速和持续的收缩， 卵巢组织，而内皮素受体拮抗剂tezosentan，释放收缩。这些新颖 这些发现使我们假设EDN-2直接收缩排卵期卵泡，导致排卵期卵泡破裂。 卵泡支持这一假设，免疫组织化学分析确定了一个组织良好的光滑 每个卵泡的外膜中的肌肉层，其在每个卵泡的外膜处形成海绵状平滑肌网络。 整个卵巢水平。此外，我们发现排卵前卵巢内注射替唑生坦 完全阻断卵泡破裂。在本研究中，我们将阐明EDN-2在卵泡中的作用机制， 破裂我们将确定EDN-2作用的靶组织，即内皮素受体亚型， 介导EDN-2作用和EDN-2的卵巢浓度。我们还将确定 内皮素-2诱导卵泡收缩与其他卵巢产生的血管紧张素分子的关系 (VIPs、PACAP和异丙肾上腺素）。此外，孕激素、雌激素和 将探索前列腺素对卵泡破裂与EDN-2的关系。这项提案的主要优点是 EDN-2和卵巢平滑肌网络是卵泡发育的关键组成部分 破裂所提出的实验的新奇是中间方法（全基因组基因 表达谱分析、卵巢内注射和等长张力测量）。拟议的研究是 这对于进一步了解卵泡破裂的机制尤为重要。的 提出的实验将为确定治疗靶点提供临床方向， 无排卵症状是女性不孕的主要原因之一。