Endothelin-2 in Ovarian Follicle Rupture

卵巢卵泡破裂中的内皮素 2

基本信息

批准号：
7763896
负责人：
Thomas E Curry
金额：
$ 22.91万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7763896
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

项目摘要

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.

拟议研究的目的是阐明内皮素 2 (EDN-2) 在卵泡中的作用机制破裂。黄体生成素的激增激活了排卵程序，从而引发了戏剧性的变化。卵巢分子、生化和物理方面的变化，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。使用基因表达谱分析方法，我们已经鉴定出 EDN-2，一种有效的平滑剂肌肉收缩蛋白，仅在排卵期的颗粒细胞中瞬时表达排卵前不久的卵泡。我们发现 EDN-2 会诱导大脑快速而持续的收缩卵巢组织，而内皮素受体拮抗剂 tezosentan 则释放收缩作用。这些小说研究结果使我们推测 EDN-2 直接收缩围排卵卵泡，导致卵泡破裂卵泡。支持这一假设的是，免疫组织化学分析发现了一个组织良好的平滑结构。每个卵泡外膜都有肌肉层，在卵泡处形成海绵状平滑肌网络整个卵巢水平。此外，我们发现在排卵前卵巢内注射 tezosentan 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、内皮素受体亚型介导 EDN-2 的作用以及 EDN-2 的卵巢浓度。我们还将确定机制内皮素 2 诱导的卵泡收缩与其他卵巢产生的血管收缩分子有关（VIP、PACAP 和前列腺素）。此外，黄体酮、雌激素和将探讨前列腺素与 EDN-2 之间的关系。该提案的主要优点鉴定 EDN-2 和卵巢平滑肌网络作为卵泡的关键组成部分破裂。所提出的实验的新颖之处在于跨学科方法（全基因组基因表达谱、卵巢内注射和等长张力测量）。拟议的研究是对于进一步了解卵泡破裂的机制非常重要。这拟议的实验将为确定治疗目标提供临床方向无排卵症状，女性不孕的主要原因之一。