Role of miR15a and miR34c in PGE2 Signaling in the Pathogenesis of Endometriosis

miR15a 和 miR34c 在 PGE2 信号传导中在子宫内膜异位症发病机制中的作用

• 批准号: 9058576
• 负责人: Joe A. Arosh
• 金额: $ 30.23万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058576
• 关键词: Acetylation; Address; Adverse effects; Age; Anabolism; Animals; Apoptosis; Apoptotic; Cell Cycle; Cell Survival; Cells; Clinical; CpG Islands; DNA Methylation; Dinoprostone; Disease; Dysmenorrhea; Endometrium; Epigenetic Process; Epithelial Cells; Estrogen Antagonists; Estrogen Therapy; Estrogens; Experimental Animal Model; Failure; Fluorescence; Future; Genomic approach; Growth; Health; Human; Hypermethylation; Hysterectomy; Infertility; Inflammation; Inflammatory; Interdisciplinary Study; Knock-in; Knowledge; Label; Lesion; Link; Mediating; Methylation; MicroRNAs; Microscopy; Mission; Molecular; Molecular Biology; National Institute of Child Health and Human Development; Pathogenesis; Pathway interactions; Patients; Peritoneal Fluid; Phase; Phenotype; Prevalence; Progesterone; Promoter Regions; Recurrence; Reproductive Health; Research Project Grants; Research Proposals; Resistance; Role; Signal Pathway; Signal Transduction; Stromal Cells; Symptoms; Techniques; Therapeutic Effect; Time; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Activation; United States; Uterine cavity; WFDC2 gene; Woman; Work; alternative treatment; base; bioimaging; chronic pelvic pain; combinatorial; cost; endometriosis; epigenetic regulation; histone modification; hormone therapy; innovation; knock-down; molecular targeted therapies; mouse model; novel; novel therapeutics; pre-clinical; prevent; receptor; reproductive

 DESCRIPTION (provided by applicant): Endometriosis is an estrogen-dependent and progesterone-resistant inflammatory disease of reproductive-age women characterized by the presence of functional endometrium outside the uterine cavity. The major symptoms of this enigmatic disease are painful menstruation, chronic pelvic pain, and infertility. Thus, it represents the single major cause for hysterectomy in reproductive-age women in United States, with annual estimated societal cost of ~$69.4 billion. Current anti-estrogen therapies can be prescribed only for a short time because of undesirable side effects and failure to prevent recurrence. Identification of novel signaling pathways that inhibit growth and survival of endometriotic lesions is needed to develop new molecular-targeted therapies for endometriosis. Concentrations of prostaglandin E2 (PGE2) in the peritoneal fluid are higher in endometriosis women compared to disease-free women, and this increased PGE2 is thought to promote the survival, growth, and inflammation of endometriosis. Expression of miR15a and miR34c appears to be epigenetically silenced in endometriotic lesions in human patients. Our overarching hypothesis is that selective inhibition of PGE2 receptors EP2 and EP4 reverses epigenetic silencing of miR15a and miR34c by altering DNA methylation and histone modifications in endometriosis and that combinatorial inhibition of EP2 and EP4 and activation of miR15a and miR34c cooperatively and synergistically inhibit growth and survival of endometriosis. Specific Aim-1 will determine the combinatorial therapeutic effects of selective inhibition of PGE2 receptors EP2 and EP4 and activation of miR15a and miR34c on growth and survival of endometriosis. Specific Aim-2 will identify the molecular and cellular mechanisms through which miR15a and miR34c mediate inhibitory effects of PGE2 receptors EP2 and EP4 on growth and survival of endometriosis. Specific Aim-3 will establish the molecular mechanisms and epigenetic pathways through which inhibition of PGE2 receptors EP2 and EP4 reverses epigenetic silencing and restores transcriptional activation of miR15a and miR34c in endometriosis. The experimental approaches such as the humanized Rag2γ(c) mice models, active human endometriotic epithelial and stromal cells, inhibition of EP2 and EP4 and activation of miR15a and miR34c by pharmacologic and genomic approaches, whole animal bioimaging, and epigenetics, molecular biology and microscopy-based techniques will be used. Successful completion of the research project is expected to provide new fundamental knowledge to formulate personalized phenotype-based combinatorial nonsteroidal therapy through inhibition of EP2 and EP4 and activation of miR15a and miR34c for endometriosis. This novel non-hormonal therapy could provide a more effective alternative treatment to existing hormonal therapies and hold promise for future innovative shifts in endometriosis treatment. Equally important, potential treatments identified in this project can be extrapolated to other inflammatory diseases. This application addresses missions of NICHD on women's reproductive health.

 描述（申请人提供）：子宫内膜异位症是育龄妇女的一种雌激素依赖性和孕激素抵抗性炎症性疾病，其特征是子宫腔外存在功能性子宫内膜。这种神秘疾病的主要症状是月经疼痛、慢性盆腔疼痛。因此，它是美国育龄妇女进行子宫切除术的唯一主要原因，目前每年的社会成本估计约为 694 亿美元。由于不良副作用和无法预防复发，抗雌激素疗法只能短期使用，因此需要确定抑制子宫内膜异位病变生长和存活的新信号通路，以开发新的子宫内膜异位症分子靶向疗法。与无子宫内膜异位症的女性相比，腹腔液中前列腺素 E2 (PGE2) 的含量更高，并且这种增加的 PGE2 被认为可以促进子宫内膜异位症的存活、生长和炎症。子宫内膜异位症患者的子宫内膜异位症病变中 miR15a 和 miR34c 的表达似乎出现表观遗传沉默，我们的总体假设是选择性抑制 PGE2 受体 EP2 和 EP4 通过改变子宫内膜异位症中的 DNA 甲基化和组蛋白修饰来逆转 miR15a 和 miR34c 的表观遗传沉默。 EP2 和 EP4 的组合抑制以及 miR15a 和 miR15a 的激活miR34c 协同并协同地抑制子宫内膜异位症的生长和存活，而特异性 Aim-1 将确定选择性抑制 PGE2 受体 EP2 和 EP4 以及激活 miR15a 和 miR34c 对子宫内膜异位症生长和存活的组合治疗效果。 miR15a和miR34c介导PGE2受体EP2和EP4对生长的抑制作用的分子和细胞机制特定的 Aim-3 将建立分子机制和表观遗传途径，通过抑制 PGE2 受体 EP2 和 EP4 逆转表观遗传沉默并恢复子宫内膜异位症中 miR15a 和 miR34c 的转录激活。 ) 小鼠模型，活性人子宫内膜异位上皮细胞和基质细胞，抑制 EP2 和 EP4 以及激活 miR15a 和将使用药理学和基因组方法、整体动物生物成像以及表观遗传学、分子生物学和基于显微镜的技术来研究 miR34c，该研究项目的成功完成预计将为通过抑制 miR34c 来制定基于表型的个性化组合非甾体疗法提供新的基础知识。 EP2 和 EP4 以及 miR15a 和 miR34c 的激活治疗子宫内膜异位症，这种新型非激素疗法可以为现有激素疗法提供更有效的替代疗法。同样重要的是，该项目中确定的潜在治疗方法可以推广到其他炎症性疾病。该应用解决了 NICHD 在妇女生殖健康方面的使命。