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（由申请人提供）：拟议研究的目的是阐明卵泡破裂中内皮素-2（EDN-2）作用的机理。排卵程序通过黄体激素激素激活，该激素引发了卵巢的分子，生化和物理方面的急剧变化，最终导致卵泡破裂。但是，涉及的因素和控制卵泡破裂过程的机制尚未公布。使用基因表达分析方法，我们已经确定了EDN-2，这是一种有效的平滑肌收缩器，在排卵前紧接在卵泡卵泡的颗粒细胞中，仅在颗粒细胞中瞬时表达。我们发现EDN-2在卵巢组织中诱导快速和持续的收缩，而内皮素受体拮抗剂Tezosentan则释放了收缩。这些新颖的发现使我们假设EDN-2直接收缩了卵泡周围卵泡，导致卵泡破裂。支持假设，免疫组织化学分析确定了每个卵泡的theca外部组织良好的平滑肌层，该卵泡在整个卵巢水平上形成了海绵状的平滑肌网络。此外，我们发现在排卵前注射了牛山山脉的内部卵泡破裂。在这项研究中，我们将阐明卵泡破裂中EDN-2作用的机制。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以及EDN-2的卵巢浓度。我们还将确定内皮素-2诱导的卵泡收缩的机理，相对于其他卵巢产生的血管收缩分子（VIP，PACAPS和Prostaglandins）。此外，还将探索孕酮，雌激素和前列腺素与相对于EDN-2的卵泡破裂的功能联系。该提案的主要优势在于将EDN-2和卵巢平滑肌网络鉴定为卵泡破裂的关键组成部分。所提出的实验的新颖性是跨学科方法（全基因组基因表达分析，摩维纳内注射和等距张力测量值）。提出的研究非常重要，以进一步了解我们对卵泡破裂机制的理解。提出的实验将提供临床方向，以识别治愈节结肠症状的治疗靶标，这是女性不育症的主要原因之一。