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.

拟议的研究的目的是阐明卵泡中内皮素-2（EDN-2）作用的机理破裂。排卵程序通过黄体生成激素激活，该激素引发了戏剧性的激素卵巢的分子，生化和物理方面的变化，最终导致破裂卵泡。但是，涉及的因素和管理卵泡破裂过程的机制尚未被公开。使用基因表达分析方法，我们已经确定了EDN-2，这是一种有效的光滑肌肉收缩器，该肌肉收缩在卵巢周围的颗粒细胞中仅瞬时表达排卵之前的卵泡。我们发现EDN-2在卵巢组织，而内皮素受体拮抗剂Tezosentan释放了收缩。这些小说调查结果使我们假设EDN-2直接收缩了卵泡周围卵泡，导致破裂卵泡。支持假设，免疫组织化学分析确定了井井有条的光滑每个卵泡的theca外部的肌肉层，在该卵泡中形成海绵状平滑肌网络整个卵巢水平。此外，我们发现在排卵前注射tezosentan 完全阻塞卵泡破裂。在这项研究中，我们将阐明卵泡中EDN-2作用的机制破裂。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与其他卵巢产生的血管约束分子相关的卵泡收缩（VIP，PACAPS和Prostaglandins）。另外，孕酮，雌激素和将探索相对于EDN-2的卵泡破裂的前列腺素。该提议的主要优势在EDN-2和卵巢平滑肌网络的鉴定中是卵泡的关键组成部分破裂。提出的实验的新颖性是跨基因方法（全基因组基因表达谱分析，载体内注射和等距张力测量）。拟议的研究是为了进一步了解卵泡破裂的机制，非常重要。这提出的实验将提供临床方向，以识别治疗的治疗靶标解除症状，是女性不育症的主要原因之一。