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: 8047065
• 负责人: Joe A. Arosh
• 金额: $ 21.59万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047065
• 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. PUBLIC HEALTH RELEVANCE: The objective of the proposed research is to determine molecular and cellular mechanisms through which selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits survival of endometriosis in order to identify PGE2 as potential nonestrogen or nonsteroidal target 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: (i) inhibit survival of endometriosis through suppressed cell survival and activated intrinsic apoptotic pathways; (ii) increase phagocytic ability of infiltrated peritoneal macrophages around endometriosis per se; (iii) inhibit local estrogen production in endometriosis; and (iv) provide exciting new knowledge that fill the gap in understanding of the pathogenesis of endometriosis. The novel findings of this project are expected to establish potential translational opportunities for treatment of endometriosis by blocking EP2 and EP4 receptors and could emerge as potential nonestrogen or nonsteroidal therapy for endometriosis in child- bearing age women.

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的药物治疗和作用未能预防疾病的复发，并影响育龄妇女的妊娠成功。这表明一个关键的需要，以确定潜在的细胞信号通路的非雌激素治疗子宫内膜异位症的目标。前列腺素E2（PGE 2）促进子宫内膜异位症的生存，然而，强调的分子机制在很大程度上是未知的。我们的长期目标是了解子宫内膜异位症发病机制中PGE 2生物合成和信号传导串扰的分子和细胞方面，以确定新的靶向治疗。本申请的目的是了解PGE 2信号通路在子宫内膜异位症的生存和发展。我们的中心假设是PGE 2受体EP 2和EP 4的功能丧失抑制了子宫内膜异位症的生存和生长。Specific Aim-1将确定EP 2和EP 4功能丧失诱导子宫内膜异位症细胞凋亡的机制。Specific Aim- 2将确定EP 2和EP 4介导的PGE 2信号传导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。具体目标-3将确定EP 2和EP 4功能丧失降低子宫内膜异位症雌激素产生的机制。我们的实验方法包括：（i）EP 2和EP 4的基因组和药理学抑制;（ii）来自子宫内膜异位症患者的稳定的荧光标记的人增生上皮细胞、基质细胞、巨噬细胞以及在位和异位内膜;（iii）裸和Rag 2g（c）小鼠异种移植模型;（v）基于分子、细胞、生物化学和显微镜的测定;以及（vi）整个动物生物成像方法。其基本原理是，成功完成拟议的研究将有助于我们的知识基础的缺失和基本元素，没有它的机制，通过选择性抑制EP 2和EP 4诱导人类前列腺增生细胞凋亡不能理解。此外，预期的结果将推进目前的子宫内膜异位症的发病机制的知识，并增加对子宫内膜异位症的生存PGE 2信号的理解。获得这些知识是至关重要的，可以转化为治疗患有子宫内膜异位症的妇女。我们预期，选择性抑制EP 2和EP 4将通过多种机制诱导子宫内膜异位症细胞的凋亡，增加子宫内膜异位症本身浸润的巨噬细胞的吞噬能力，并减少子宫内膜异位症细胞的雌激素产生。我们的研究结果将具有临床影响，因为它将首次允许开发新的和急需的治疗策略，以抑制EP 2和EP 4信号传导作为治疗育龄妇女子宫内膜异位症的新型非雌激素靶点。这是一个R21应用程序，涉及NIH/NICHD在妇女生殖健康方面的使命。 公共卫生关系：该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生存的分子和细胞机制，以确定PGE 2作为治疗女性子宫内膜异位症的潜在非雌激素或非甾体靶点。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：（i）通过抑制细胞存活和激活内在凋亡途径抑制子宫内膜异位症的存活;（ii）增加子宫内膜异位症本身周围浸润的腹腔巨噬细胞的吞噬能力;（iii）抑制子宫内膜异位症中局部雌激素的产生;（iv）抑制子宫内膜异位症中局部雌激素的产生。和（iv）提供令人兴奋的新知识，填补了对子宫内膜异位症发病机制理解的差距。该项目的新发现有望通过阻断EP 2和EP 4受体为治疗子宫内膜异位症建立潜在的转化机会，并可能成为育龄妇女子宫内膜异位症的潜在非雌激素或非甾体治疗。