Prostaglandin E2 Signaling in Growth and Pains of Endometriosis

前列腺素 E2 信号在子宫内膜异位症生长和疼痛中的作用

• 批准号: 8191447
• 负责人: Joe A. Arosh
• 金额: $ 21.98万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-06 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191447
• 关键词: Abbreviations; Address; Adverse effects; Age; Anabolism; Analgesics; Anatomy; Androgens; Animal Model; Animals; Aromatase Inhibitors; Behavioral; Biochemical; Biological Assay; Bone Density; Cells; Clinical; Data; Development; Dinoprostone; Disease; Dysmenorrhea; EP4 receptor; Endometrial; Endometrium; Epithelial Cells; Estrogen Antagonists; Estrogen Therapy; Estrogens; Fluorescence; Genomics; Goals; Gonadotropin-Releasing Hormone Analog; Growth; Health; Hemorrhage; Human; Hypersensitivity; Implant; In Vitro; Infertility; Inflammation; Inflammatory; Interdisciplinary Study; Interleukins; Knowledge; Label; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Medical; Membrane; Microscopy; Mission; Modeling; Molecular; Mus; Myocardial Infarction; National Institute of Child Health and Human Development; Nerve; Nerve Growth Factors; Neuropeptides; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Oral Contraceptives; Outcome; Ovarian Ablation; PTGS2 gene; Pain; Pathogenesis; Pathologist; Patients; Pelvic Pain; Perception; Peripheral; Peripheral Nerves; Play; Posterior Horn Cells; Pregnancy; Prevalence; Production; Publishing; Reproduction; Research; Research Project Grants; Risk; Role; Signal Pathway; Signal Transduction; Site; Stomach; Stream; Stroke; Stromal Cells; Symptoms; Synapses; Testing; Time; Tissues; Translating; Tumor Necrosis Factor-alpha; Ulcer; United States National Institutes of Health; Uterine Cancer; Uterine cavity; Woman; Work; Xenograft procedure; base; bioimaging; central sensitization; clinical application; cytokine; endometriosis; human WFDC2 protein; in vivo Model; inhibitor/antagonist; innovation; knock-down; loss of function; nerve supply; novel; novel strategies; pain behavior; prostaglandin EP2 receptor; prostaglandin EP3 receptor; prostanoid receptor EP1; receptor; relating to nervous system; reproductive; response; therapeutic target

DESCRIPTION (provided by applicant): Endometriosis is an inflammatory disease characterized by the presence of functional endometrium outside the uterine cavity. The major two symptoms are intolerable pelvic pain and infertility. Prostaglandin E2 (PGE2) plays important roles in the pathogenesis of endometriosis. PGE2 is the principal mediator in inflammation and pain hypersensitivity. Inhibition of PGE2 biosynthesis using NSAIDs and COX-2 inhibitors has emerged as the main class analgesics. However, clinical use of NSAIDs produces unwanted side effects such as gastric erosion, ulceration, and hemorrhage, and prolonged use of COX-2-selective inhibitors confers a risk for myocardial infarction and stroke. PGE2 produced at the site of inflammation acts on the nociceptors of peripheral terminals through EP1, EP2, EP3, and EP4 receptors by integrating multiple cell signaling pathways. Selective inhibition of PGE2 signaling as therapeutic targets down-stream of COX-2 may provide an opportunity to inhibit pro-nociceptive actions of PGE2 in the pathogenesis of endometriosis. Our long-term goal is to understand molecular and cellular aspects of PGE2 in the pathogenesis and pain of endometriosis with the aim of identifying PGE2receptors as non-steroidal targets for the treatment of endometriosis. The objective of this application is to understand PGE2 signaling in growth and pain of endometriosis. The central hypothesis is that selective inhibition of prostaglandin E2 signaling decreases pain of endometriosis through inhibition of growth of endometriotic cells and development of nociceptive mechanisms. Specific Aim 1 will determine the effects of systemic blockade of EP2 and EP4 receptors on growth, innervations, and pain of endometriosis. Specific Aim-2 will determine molecular mechanisms of through which cell specific knock-down of EP2 and EP4 in endometriotic epithelial and stromal cells inhibits development of innervations and nociceptive mechanisms of endometriosis. Effects of selective inhibition of EP2 and EP4 on growth, innervations, and pain of endometriosis will be determined using genomic, pharmacological, molecular, cellular, biochemical, microscopy, and bioimaging approaches, and xenograft Rag23(c) mice and pain behavior animal models. The proposed work is innovative: (i) because it capitalizes on a new means of identifying PGE2 signaling in the pathogenesis of endometriosis and induction of endometriosis pain, and (ii) expected to decrease pain of endometriosis through inhibition of growth of endometriotic cells, innervations of endometriosis, and development of peripheral and central nociceptive mechanisms. This highly significant advancement in our understanding of endometriosis will provide the knowledge needed to translate selective inhibition of EP2 and EP4 into clinical application as a potential novel non-steroidal therapy for endometriosis in women. In addition, the expected results will fill the substantial gap in the current knowledge of the pathogenesis of endometriosis and perception of endometriosis pain. This is a R21 application addresses the mission of NIH/NICHD on women's reproduction health. PUBLIC HEALTH RELEVANCE: The objectives of the proposed research are to determine molecular and cellular mechanisms through which selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits growth of endometriosis and endometriosis-induced pain and to develop EP2 and EP4 inhibitors as new non-steroidal targets for the treatment of endometriosis in women. The expected outcomes of this project are that selective inhibition of EP2 and EP4-mediated PGE2 signaling will decrease growth and pain of endometriosis and fill the substantial gap in the current knowledge of the pathogenesis of endometriosis and perception of endometriosis pain. This highly significant advancement in our understanding of endometriosis will provide the knowledge needed to translate selective inhibition of EP2 and EP4 into clinical application as a potential novel non-steroidal therapy for endometriosis in women.

描述（由申请人提供）：子宫内膜异位症是一种炎症性疾病，其特征是子宫腔外存在功能性子宫内膜。主要的两个症状是无法忍受的盆腔疼痛和不孕症。前列腺素E2（PGE 2）在子宫内膜异位症的发病中起重要作用。PGE 2是炎症和疼痛超敏反应的主要介质。使用NSAID和考克斯-2抑制剂抑制PGE 2生物合成已成为主要的镇痛剂类别。然而，NSAID的临床使用产生不希望的副作用，例如胃糜烂、溃疡和出血，并且长期使用考克斯-2选择性抑制剂赋予心肌梗塞和中风的风险。炎症部位产生的PGE 2通过整合多种细胞信号通路，通过EP 1、EP 2、EP 3和EP 4受体作用于外周末梢的伤害感受器。选择性抑制PGE 2信号传导作为考克斯-2下游的治疗靶点可能提供抑制PGE 2在子宫内膜异位症发病机制中的促伤害感受作用的机会。我们的长期目标是了解PGE 2在子宫内膜异位症发病机制和疼痛中的分子和细胞方面，目的是确定PGE 2受体作为治疗子宫内膜异位症的非甾体靶点。本申请的目的是了解PGE 2信号在子宫内膜异位症的生长和疼痛。中心假设是选择性抑制前列腺素E2信号通过抑制增生细胞的生长和伤害性机制的发展来减轻子宫内膜异位症的疼痛。具体目标1将确定全身阻断EP 2和EP 4受体对子宫内膜异位症的生长、神经支配和疼痛的影响。特异性Aim-2将确定细胞特异性敲低子宫内膜异位上皮细胞和基质细胞中的EP 2和EP 4抑制神经支配和子宫内膜异位症伤害感受机制发展的分子机制。将使用基因组、药理学、分子、细胞、生物化学、显微镜和生物成像方法以及异种移植Rag 23（c）小鼠和疼痛行为动物模型来确定选择性抑制EP 2和EP 4对子宫内膜异位症的生长、神经支配和疼痛的影响。拟议的工作是创新的：（i）因为它利用了一种新的方法来识别子宫内膜异位症发病机制中的PGE 2信号传导和子宫内膜异位症疼痛的诱导，以及（ii）预计通过抑制子宫内膜异位症细胞的生长，子宫内膜异位症的神经支配以及外周和中枢伤害性机制的发展来减少子宫内膜异位症的疼痛。我们对子宫内膜异位症的理解的这一高度显著的进步将提供将选择性抑制EP 2和EP 4转化为临床应用所需的知识，作为女性子宫内膜异位症的潜在新型非甾体疗法。此外，预期的结果将填补目前对子宫内膜异位症发病机制和子宫内膜异位症疼痛感知的知识空白。这是一个R21应用程序，解决了NIH/NICHD在妇女生殖健康方面的使命。 公共卫生相关性：拟议研究的目的是确定选择性抑制前列腺素E2（PGE 2）受体EP 2和EP 4抑制子宫内膜异位症和子宫内膜异位症引起的疼痛的分子和细胞机制，并开发EP 2和EP 4抑制剂作为治疗女性子宫内膜异位症的新的非甾体靶点。该项目的预期结果是，选择性抑制EP 2和EP 4介导的PGE 2信号传导将减少子宫内膜异位症的生长和疼痛，并填补了目前对子宫内膜异位症发病机制和子宫内膜异位症疼痛感知的知识空白。我们对子宫内膜异位症的理解的这一高度显著的进步将提供将选择性抑制EP 2和EP 4转化为临床应用所需的知识，作为女性子宫内膜异位症的潜在新型非甾体疗法。