Role of microRNA in the Pathophysiology of Endometriosis

microRNA 在子宫内膜异位症病理生理学中的作用

基本信息

批准号：
9027109
负责人：
Asgerally T. Fazleabas
金额：
$ 33.61万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027109
关键词：
Affect Age Automobile Driving Binding Biogenesis Bioinformatics Biology Cell Proliferation Cells Clinical Complex DNA Data Decidual Cell Reactions Deposition Development Diagnosis Diagnostic Disease Disease Progression Down-Regulation Endometrial Endometrium Environment Epigenetic Process Etiology Event Extracellular Matrix FOS gene Fibrosis Figs - dietary Functional disorder Gene Expression Regulation Gene Targeting Genes Gland Human Incidence Infertility Inflammation Insulin-Like Growth-Factor Binding Protein 1 Lead Lesion Link MAPK3 gene Mediating Methylation MicroRNAs Modeling Molecular Myofibroblast PTGS2 gene Pain Papio Pathogenesis Pathology Pathway interactions Pattern Phenotype Play Progesterone Promoter Regions Proteins Regulation Reporting Resistance Role Signal Transduction Site Smooth Muscle Actin Staining Method Stromal Cells Testing Therapeutic Time Tissues Transcription Factor AP-1 Untranslated RNA Up-Regulation Uterine cavity Woman Work base beta catenin chronic pelvic pain clinical Diagnosis decorin early onset endometriosis estrogenic human disease human tissue improved innovation migration promoter public health relevance reproductive response tacrolimus binding protein 4 uterine receptivity

项目摘要

DESCRIPTION (provided by applicant): Endometriosis, the presence of endometrial glands and stroma outside of the uterine cavity causes chronic pelvic pain and infertility. It affects 10% of women of reproductive age and 35-50% of women who are infertile. The average time for confirmed clinical diagnosis takes between 8-11 years and the molecular mechanisms associated with the pathophysiology of endometriosis still remains poorly understood. Our extensive studies over the past 20 years have characterized the causative factors and molecular changes that are involved in the early onset of disease in a baboon model of experimentally induced endometriosis. MicroRNAs (miR) which are small non-coding RNAs that regulate posttranscriptional gene regulation, have emerged as important regulators that may contribute to pathophysiology of endometriosis. Our preliminary data suggests that induction of endometriosis leads to rapid and significant changes in the expression of several miRs in the baboon. MiR-451 together with miR-144 which is expressed at the same gene locus were significantly down regulated, while miR-21 and miR-29c showed a progressive increase following induction of endometriosis in both ectopic and eutopic tissues. Similar changes have been reported in women with disease. Changes in miR expression which we hypothesize are transcriptionally induced as a consequence of the disease, are associated with the corresponding alterations of their respective target genes, YWHAZ, FKBP4, 15-PGDH and fibrosis. We propose that these changes contribute to the progression of endometriosis and altered endometrial function. To test these hypotheses, in Specific Aim 1 we propose to determine if c-Fos regulation of AP-1 sites on the miR gene promoter, epigenetic changes (methylation) and increased Dicer activity associated with endometriosis is responsible for the aberrant miR expression in the eutopic and ectopic endometrium. In Specific Aim 2 we will validate the regulation of target genes YWHAZ/β−catenin by miR-451 to promote proliferation and invasion by interacting with Yes-associated protein (YAP1). Aim 3 focuses on the mechanisms by which miR-29c regulates FKBP4 which imparts progesterone resistance and results in a blunted decidualization response. The inhibition of decidualization will be assessed by the validating the expression of decorin and insulin-like growth factor binding protein-1. Specific Aim 4 will focus on the role of miR-21 in contributing to the development of fibrosis in endometriotic lesions and its potential role in mediating COX-2 mediated inflammation. These innovative studies will contribute to our understanding of the molecular mechanisms underlying the etiology of endometriosis. The proposed aims will functionally link aberrant miR expression, induced in response to the disease, with their respective target genes that induce changes in the eutopic and ectopic endometrium that are pathologically relevant in the etiology of endometriosis.

描述（通过应用提供）：子宫内膜异位症，子宫内膜腺体和子宫腔外的基质的存在会导致慢性骨盆疼痛和不育。它影响10％确认的临床诊断的平均时间需要在8 - 11年之间，并且与子宫内膜异位症的病理生理学相关的分子机制仍然很少了解。在过去的20年中，我们的广泛研究表征了在实验诱导的子宫内膜异位症模型中疾病早期发作所涉及的严重因素和分子变化。 MicroRNA（miR）是调节转录后基因调控的小型非编码RNA，已成为重要的调节剂，可能有助于子宫内膜异位的病理生理。我们的初步数据表明，子宫内膜异位症的诱导会导致狒狒中几种miR的表达快速而显着变化。 miR-451与在同一基因基因座上表达的miR-144一起被显着下调，而在依托比亚和精神组织中子宫内膜异位症诱导后，miR-21和miR-29c均显示出逐渐增加。疾病女性也报道了类似的变化。我们假设的miR表达的变化是由于疾病而在转录诱导的，与它们各自的靶基因YWHAZ，FKBP4，15-PGDH和纤维化的相应变化有关。我们建议这些变化有助于子宫内膜异位症和子宫内膜功能的改变。为了检验这些假设，在特定目标1中，我们建议确定miR基因启动子上AP-1位点，表观遗传变化（甲基化）以及与子宫内膜异位症相关的丁香活性增加是否负责Eutopic和Eopic entormetrium中异常miR的异常表达。在特定的目标2中，我们将通过miR-451验证靶基因YWHAZ/β-catenin的调节，以通过与YES相关蛋白（YAP1）相互作用来促进增殖和侵袭。 AIM 3的重点是miR-29c调节FKBP4的机制，该机制冒犯了孕激素的耐药性并导致决策反应钝。决策的抑制作用将通过验证Decorin和胰岛素样生长因子结合蛋白-1的表达来评估。具体目标4将集中于miR-21在子宫内膜病变中纤维化发展及其在介导COX-2介导的感染中的潜在作用的作用。这些创新的研究将有助于我们理解子宫内膜异位症病因的分子机制。拟议的目标将在功能上将响应于该疾病的诱导的异常miR表达与它们的各自的靶基因诱导，这些基因影响了在子宫内膜异位症的病因中具有病理学相关的Eutopic和Etopic子宫内膜变化。