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

• 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
• 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

 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（由申请人提供）：子宫内膜异位症，子宫内膜腺体和子宫腔外基质的存在导致慢性盆腔疼痛和不孕。影响10% 35-50%的育龄妇女和35-50%的不孕妇女。临床确诊的平均时间为8-11年，与子宫内膜异位症病理生理学相关的分子机制仍然知之甚少。我们在过去20年的广泛研究已经确定了实验诱导的子宫内膜异位症狒狒模型中疾病早期发作的致病因素和分子变化。MicroRNAs（miR）是一类调控转录后基因表达的非编码小分子RNA，在子宫内膜异位症的发病机制中起重要作用。我们的初步数据表明，子宫内膜异位症的诱导导致狒狒中几种miR表达的快速和显著变化。在异位和在位组织中，miR-451与在相同基因位点表达的miR-144一起显著下调，而miR-21和miR-29 c在诱导子宫内膜异位症后显示进行性增加。据报道，在患病妇女中也出现了类似的变化。我们假设miR表达的变化是由疾病引起的转录诱导的，与其各自靶基因YWHAZ、FKBP 4、15-PGDH和纤维化的相应改变相关。我们认为这些变化有助于子宫内膜异位症的进展和子宫内膜功能的改变。为了验证这些假设，在具体目标1中，我们建议确定miR基因启动子上AP-1位点的c-Fos调控、与子宫内膜异位症相关的表观遗传变化（甲基化）和Dicer活性增加是否是在位和异位子宫内膜中异常miR表达的原因。在具体目标2中，我们将验证miR-451对靶基因YWHAZ/β-catenin的调控，通过与YAP 1相互作用促进增殖和侵袭。目的3关注miR-29 c调节FKBP 4的机制，FKBP 4赋予孕酮抗性并导致钝化的蜕膜化反应。通过验证核心蛋白聚糖和胰岛素样生长因子结合蛋白-1的表达来评估对蜕膜化的抑制。具体目标4将重点关注miR-21在促进增生性病变中纤维化发展中的作用及其在介导考克斯-2介导的炎症中的潜在作用。这些创新的研究将有助于我们了解子宫内膜异位症的病因学的分子机制。所提出的目标将功能性地将响应于疾病而诱导的异常miR表达与其各自的靶基因相联系，所述靶基因诱导在子宫内膜异位症的病因学中病理相关的在位和异位子宫内膜的变化。