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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：子宫内膜异位症是一种雌激素依赖性和孕激素耐药性疾病的生殖年龄妇女，其特征是子宫腔外有功能性子宫内膜。这种神秘疾病的主要症状是疼痛的月经，慢性骨盆疼痛和不育。这是美国生殖年龄妇女子宫切除术的单一主要原因，年度估计的社会意式成本约为694亿美元。当前的抗雌激素疗法只能在短时间内开处方，这是由于不良的副作用和无法预防复发的情况。需要确定抑制子宫内膜病变生长和存活的新型信号通路，以开发新的分子靶向子宫内膜异位症。与无病女性相比，子宫内膜异位女性的腹膜液中前列腺素E2（PGE2）的浓度更高，并且这种增加的PGE2被认为可以促进子宫内膜异位症的生存，生长和炎症。 MiR15a和MiR34C的表达似乎在人类患者的子宫内膜损伤中表观遗传沉默。 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.具体的AIM-1将确定对PGE2受体EP2和EP4的选择性抑制以及MiR15a和MiR34C对子宫内膜异位症的生长和存活的组合治疗作用。特定的AIM-2将确定MIR15A和MIR34C介导PGE2受体EP2和EP4对子宫内膜异位症生长和存活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，通过该途径，PGE2受体EP2和EP4的抑制会逆转表观遗传沉默，并恢复子宫内膜异位中miR15a和miR34C的转录激活。实验方法，例如人源化RAG2γ（C）小鼠模型，活性的人子宫内膜内核上皮细胞和基质细胞，通过药物和基因组方法抑制EP2和EP4以及MiR15a和MiR34C的激活，全动物生物成像，整个动物生物成像，以及表观遗传学，分子生物学和显微镜技术。预计该研究项目的成功完成将提供新的基本知识，以通过抑制EP2和EP4的抑制以及MIR15A和MIR34C的激活来制定基于个性化表型的非甾体类治疗，以用于子宫内膜异位症。这种新型的非荷尔蒙治疗可以为现有的Horseal疗法提供更有效的替代疗法，并有望在子宫内膜异位症治疗中未来的创新转变。同样重要的是，该项目中确定的潜在治疗方法可以推断到其他炎症性疾病。该申请介绍了NICHD关于妇女复制健康的任务。