Molecular Basis of Treating Endometriosis by Prostaglandin E2 Receptor Inhibitors

前列腺素E2受体抑制剂治疗子宫内膜异位症的分子基础

• 批准号: 8324484
• 负责人: Joe A. Arosh
• 金额: $ 17.93万
• 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: 2011-08-25 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324484
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Abbreviations; Address; Affect; Age; Anabolism; Anatomy; Animal Model; Animals; Apoptosis; Apoptotic; Aromatase; Biochemical; Biological Assay; CD36 gene; Cell Survival; Cell physiology; Cells; Clinical; Cytochrome P450; Data; Dinoprostone; Disease; EP4 receptor; Elements; Emotional; Endocrinologist; Endometrium; Epithelial Cells; Estradiol; Estrogens; Female of child bearing age; Fluorescence; Genomics; Goals; Growth; Human; Immune; In Vitro; Infertility; Inflammation; Inflammatory; Interdisciplinary Study; Knowledge; Label; MAPK3 gene; Mediating; Medical; Menstruation; Methods; Microscopy; Mission; Modality; Modeling; Molecular; Mus; National Institute of Child Health and Human Development; Outcome; Pain; Pathogenesis; Pathologist; Pathway interactions; Patients; Pelvic Pain; Peritoneal Fluid; Peritoneal Macrophages; Personal Satisfaction; Phagocytosis; Pregnancy; Production; Proto-Oncogene Proteins c-akt; Quality of life; Recurrence; Reproductive Health; Research; Research Project Grants; Signal Pathway; Signal Transduction; Stromal Cells; Testing; Therapeutic; Time; Translating; United States National Institutes of Health; Uterine cavity; Woman; Work; Xenograft Model; base; bioimaging; caspase-3; endometriosis; expectation; human WFDC2 protein; in vivo; inhibitor/antagonist; innovation; knowledge base; loss of function; macrophage; monocyte; novel; novel strategies; prevent; prostaglandin EP2 receptor; protein expression; receptor; reproductive; success; therapeutic target

DESCRIPTION (provided by applicant): Endometriosis is an estrogen dependent disease. Current medical therapies to inhibit estrogen biosynthesis and actions fail to prevent reoccurrence of the disease and compromise success of pregnancy in child-bearing age women. This suggests a crucial need to identify potential cell signaling pathways for nonestrogen therapeutic targets for endometriosis. Prostaglandin E2 (PGE2) promotes survival of endometriosis, however; the underlined molecular mechanisms are largely unknown. Our long-term goal is to understand molecular and cellular aspects of PGE2 biosynthesis and signaling cross-talk in the pathogenesis of endometriosis in order to identify new targeted therapies. The objective of this application is to understand PGE2 signaling pathways in survival and growth of endometriosis. Our central hypothesis is that loss-of-function of PGE2 receptors EP2 and EP4 inhibits survival and growth of endometriosis. Specific Aim-1 will determine the mechanisms through which loss-of-function of EP2 and EP4 induces apoptosis of endometriosis. Specific Aim- 2 will determine the mechanisms through which EP2 and EP4-mediated PGE2 signaling immunomodulate and enhance the phagocytic ability of macrophages in endometriosis. Specific Aim-3 will determine the mechanisms through which loss-of-function of EP2 and EP4 decrease estrogen production in endometriosis. Our experimental approaches include: (i) genomic and pharmacological inhibition of EP2 and EP4; (ii) stable fluorescence-labeled human endometriotic epithelial cells, stromal cells, macrophages, and eutopic and ectopic endometria from endometriosis patients, (iii) nude and Rag2g(c) mice xenograft models, (v) molecular, cellular, biochemical, and microscopy-based assays; and (vi) whole animal bioimaging method. The rationale is that successful completion of the proposed research will contribute a missing and fundamental element to our base of knowledge without which the mechanism through which selective inhibition of EP2 and EP4 induces apoptosis of human endometriotic cells cannot be understood. In addition, the expected results will advance the current knowledge of the pathogenesis of endometriosis and increase the understanding of PGE2 signaling in survival of endometriosis. The acquisition of such knowledge is critical and could be translated to treat women suffering from endometriosis. It is our expectation that selective inhibition of EP2 and EP4 will induce apoptosis of endometriotic cells, increase phagocytic ability of infiltrated macrophages in endometriosis per se, and decrease estrogen production by the endometriotic cells through multiple mechanisms. Our findings would have clinical impact because it would allow for the first time to develop new and much needed therapeutic strategies to inhibit EP2 and EP4 signaling as novel nonestrogen targets for the treatment of endometriosis in child-bearing age women. This is a R21 application addresses the mission of NIH/NICHD on women's reproductive health.

描述（由申请人提供）：子宫内膜异位症是一种雌激素依赖性疾病。目前抑制雌激素生物合成和作用的医学疗法无法防止疾病复发并影响育龄妇女怀孕的成功。这表明迫切需要确定子宫内膜异位症非雌激素治疗靶点的潜在细胞信号传导途径。然而，前列腺素 E2 (PGE2) 可促进子宫内膜异位症的存活；下划线的分子机制很大程度上是未知的。我们的长期目标是了解 PGE2 生物合成的分子和细胞方面以及子宫内膜异位症发病机制中的信号串扰，以便确定新的靶向疗法。本应用的目的是了解子宫内膜异位症存活和生长中的 PGE2 信号通路。我们的中心假设是 PGE2 受体 EP2 和 EP4 功能丧失会抑制子宫内膜异位症的存活和生长。特定的 Aim-1 将确定 EP2 和 EP4 功能丧失诱导子宫内膜异位症细胞凋亡的机制。具体目标2将确定EP2和EP4介导的PGE2信号免疫调节和增强子宫内膜异位症中巨噬细胞吞噬能力的机制。具体的 Aim-3 将确定 EP2 和 EP4 功能丧失减少子宫内膜异位症中雌激素产生的机制。我们的实验方法包括：(i) EP2 和 EP4 的基因组和药理学抑制； (ii) 稳定荧光标记的人子宫内膜异位症上皮细胞、基质细胞、巨噬细胞以及来自子宫内膜异位症患者的在位和异位子宫内膜，(iii) 裸鼠和 Rag2g(c) 小鼠异种移植模型，(v) 分子、细胞、生化和显微镜检查基于分析； (vi) 整体动物生物成像方法。其基本原理是，成功完成拟议的研究将为我们的知识基础贡献一个缺失的基本要素，否则就无法理解选择性抑制 EP2 和 EP4 诱导人类子宫内膜异位细胞凋亡的机制。此外，预期结果将推进目前对子宫内膜异位症发病机制的认识，并增加对子宫内膜异位症生存中 PGE2 信号传导的理解。获得这些知识至关重要，可以转化为治疗患有子宫内膜异位症的妇女。我们期望选择性抑制EP2和EP4将诱导子宫内膜异位细胞凋亡，增加子宫内膜异位症本身浸润巨噬细胞的吞噬能力，​​并通过多种机制减少子宫内膜异位细胞产生雌激素。我们的研究结果将产生临床影响，因为它将首次允许开发新的、急需的治疗策略来抑制 EP2 和 EP4 信号传导，作为治疗育龄妇女子宫内膜异位症的新非雌激素靶点。这是 R21 应用程序，旨在体现 NIH/NICHD 在妇女生殖健康方面的使命。