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

基本信息

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
项目类别：
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

项目摘要

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依赖雌激素的疾病。当前抑制雌激素生物合成和作用的医疗疗法无法防止这种疾病的再发生，并损害了育儿女性怀孕的成功。这表明至关重要的需要确定子宫内膜异位症的非雌激素治疗靶标的潜在细胞信号传导途径。然而，前列腺素E2（PGE2）促进了子宫内膜异位症的生存。下划线的分子机制在很大程度上未知。我们的长期目标是了解子宫内膜异位症发病机理中PGE2生物合成和信号传导交叉对话的分子和细胞方面，以鉴定新的靶向疗法。该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的功能丧失抑制了子宫内膜异位症的存活和生长。具体的AIM-1将确定EP2和EP4功能丧失的机制可诱导子宫内膜异位症的凋亡。特定的目标2将确定EP2和EP4介导的PGE2信号传导免疫调节并增强巨噬细胞在子宫内膜异位症中的吞噬能力的机制。特定的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的基因组和药理抑制；（ii）从子宫内膜异位症患者（III）裸体和RAG2G（c）小鼠异位属性模型，（v）分子，细胞，生物学，生物化学基础和基于显微镜基于基因，裸体和RAG2G（iii）裸体和RAG2G（III）裸体和RAG2G（iii）裸体和RAG2G（c），稳定的荧光标记的人子宫内膜细胞，基质细胞，巨噬细胞，巨噬细胞以及EUTOPIC和异位内部测量。（vi）整个动物生物成像方法。理由是，成功完成拟议的研究将为我们的知识基础贡献一个缺失和基本要素，而没有这种机制可以理解对EP2和EP4的选择性抑制诱导人类子宫内膜细胞的凋亡。此外，预期的结果将推进当前对子宫内膜异位发病机理的了解，并增加对子宫内膜异位症存活中PGE2信号传导的理解。获取此类知识至关重要，可以转化为治疗患有子宫内膜异位症的妇女。我们期望对EP2和EP4的选择性抑制作用会诱导子宫内膜细胞的凋亡，增加子宫内膜异位症本质上浸润的巨噬细胞的吞噬能力，并通过多种机制降低子宫内膜细胞的雌激素产生。我们的发现将产生临床影响，因为它将首次开发新的急需的治疗策略，以抑制EP2和EP4信号作为治疗子宫内膜异位症的新型非雌激素靶标，以抑制子宫内膜异位症。这是R21申请，涉及NIH/NICHD在妇女生殖健康方面的任务。