Role of microRNA in the Pathophysiology of Endometriosis

 描述(申请人提供)：子宫内膜异位症，子宫内膜腺和子宫腔外间质的存在会导致慢性盆腔疼痛和不孕症。它会影响10% 育龄妇女和35%-50%的不孕不育妇女。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。在过去的20年里，我们进行了广泛的研究，确定了在实验诱导的恒河猴子宫内膜异位症模型中，早期发病所涉及的致病因素和分子变化。MicroRNAs(MiR)是一种调节转录后基因调控的非编码小RNA，已成为子宫内膜异位症病理生理过程中的重要调节因子。我们的初步数据表明，子宫内膜异位症的诱导会导致狒狒体内几个miRs表达的快速而显著的变化。在异位和在位组织中，miR-451和miR-144表达均显著下调，miR-21和miR-29c表达均呈进行性升高。据报道，患有疾病的女性也出现了类似的变化。我们假设miR表达的变化是由于疾病的转录诱导的，与它们各自的靶基因YWHAZ、FKBP4、15-PGDH和纤维化的相应变化有关。我们认为这些改变有助于子宫内膜异位症的进展和子宫内膜功能的改变。为了验证这些假说，在特定的目标1中，我们建议确定miR基因启动子上AP-1位点的c-Fos调节、表观遗传学改变(甲基化)和与子宫内膜异位症相关的Dird活性增加是否与在位和异位内膜中miR的异常表达有关。在特定目的2中，我们将验证miR-451对靶基因YWHAZ/β−连环蛋白的调控，通过与YAP1相互作用促进细胞增殖和侵袭。目的3重点研究miR-29c调节FKBP4的机制，FKBP4传递孕激素抵抗并导致迟钝的蜕膜化反应。蜕膜化的抑制作用将通过验证核心蛋白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将集中在miR-21在促进子宫内膜异位症纤维化发展中的作用以及它在介导COX-2介导的炎症中的潜在作用。这些创新性的研究将有助于我们理解子宫内膜异位症发病的分子机制。拟议的AIMS将在功能上将因疾病而诱导的miR异常表达与其各自的靶基因联系起来，这些靶基因导致在位和异位内膜发生变化，这些变化在子宫内膜异位症的病因中具有病理学意义。

 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.