Endothelin-2 in Ovarian Follicle Rupture

卵巢卵泡破裂中的内皮素 2

• 批准号: 7232265
• 负责人: CHEMYONG JAY KO
• 金额: $ 23.61万
• 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/7232265
• 关键词: Animal Model; BQ123; Binding Sites; Biochemical; Biochemical Process; Clinical; Constriction procedure; Count; 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; Genome; 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; Numbers; Oocytes; Ovarian; Ovarian Diseases; Ovarian Follicle; Ovarian Tissue; Ovary; Ovulation; PTGS2 gene; Pattern; Pituitary Gonadotropins; Porifera; Process; Progesterone; Progesterone Receptors; Prostaglandin Receptor; Prostaglandins; RU-486; Radioimmunoassay; Rattus; Research Personnel; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Role; Rupture; Smooth Muscle; Structure; Symptoms; Syndrome; System; Techniques; Theca Externa; Therapeutic; Tissues; Vasoactive Intestinal Peptide; corpus luteum; granulosa cell; in vivo; inhibitor/antagonist; interdisciplinary approach; intraovarian; novel; programs; receptor; research study; tezosentan; therapeutic target

DESCRIPTION (provided by applicant): 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 vasoconstrictive 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 interdisciplinary approaches (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.

描述（由申请方提供）：拟定研究的目的是阐明内皮素-2（EDN-2）在卵泡破裂中的作用机制。促黄体生成激素的激增激活了排卵程序，这引发了卵巢分子，生化和物理方面的巨大变化，最终导致卵泡破裂。然而，卵泡破裂过程中的因素和机制尚未被揭示。使用基因表达谱的方法，我们已经确定了EDN-2，一个强大的平滑肌收缩，这是专门和瞬时表达的颗粒细胞排卵前立即排卵卵泡。我们发现，EDN-2诱导卵巢组织快速和持续的收缩，而内皮素受体拮抗剂tezosentan，释放收缩。这些新的发现使我们假设EDN-2直接收缩排卵期卵泡，导致卵泡破裂。支持这一假设，免疫组化分析确定了一个组织良好的平滑肌层，在每个卵泡的外膜，形成一个海绵状平滑肌网络在整个卵巢水平。此外，我们发现在排卵前卵巢内注射替唑生坦完全阻断了卵泡破裂。在本研究中，我们将阐明EDN-2在卵泡破裂中的作用机制。我们将确定EDN-2作用的靶组织、介导EDN-2作用的内皮素受体亚型和EDN-2的卵巢浓度。我们还将确定内皮素-2诱导卵泡收缩的机制与其他卵巢产生的血管收缩分子（VIP，PACAP，和Eschlandins）。此外，孕酮，雌激素和前列腺素与EDN-2相关的卵泡破裂的功能联系将被探索。该建议的主要优势在于将EDN-2和卵巢平滑肌网络鉴定为卵泡破裂的关键组分。所提出的实验的新奇是跨学科的方法（全基因组基因表达谱，卵巢内注射，等长张力测量）。这些研究对于进一步了解卵泡破裂的机制具有重要意义。拟议的实验将为确定治疗无排卵症状的治疗靶点提供临床方向，无排卵症状是女性不孕症的主要原因之一。