Role of MicroRNA 451 in the Pathophysiology 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。临床诊断平均需要8-11年，与病理生理学相关的分子机制仍然知之甚少。我们的实验室在过去的12年里进行了开创性的研究，在此期间，我们已经确定了实验诱导子宫内膜异位症的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，诱导子宫内膜异位症导致快速和显着的变化，在几个miR的表达。本申请特别关注在子宫内膜异位症诱导后高度下调的miR-451的生物学功能。miR表达的变化反映在其靶基因YWHAZ的相应改变中。我们推测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。为了验证这一假设，我们在特定目标1中提出了确定YWHAZ与β-连环蛋白形成复合物以促进细胞增殖和迁移以及凋亡的机制。在具体目标2中，我们将专注于免疫功能低下小鼠的异种移植实验和体内miR模拟物，抑制剂和siRNA的靶向递送，以测试使用基于miR的治疗方法治疗子宫内膜异位症的疗效。这些创新的研究将有助于我们了解子宫内膜异位症病因学的分子机制，并在功能上将miR表达与病理相关的靶基因联系起来。

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% who are infertile. The average for clinical diagnosis takes 8-11 years and the molecular mechanisms associated with the pathophysiology still remains poorly understood. Our laboratory has undertaken pioneering research in the past 12 years during which we have characterized the causative factors and molecular changes that are involved in the early onset of the disease in a baboon model of experimentally induced endometriosis. MicroRNAs (miR), small non-coding RNAs which 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. This application focuses specifically on the biological functions of miR-451 that is highly down regulated following induction of endometriosis. Changes in miR expression were reflected in the corresponding alterations of its target gene, YWHAZ. We hypothesize that these changes contribute to the progression of endometriosis and altered endometrial function. To test this hypothesis in Specific Aim 1 we propose to the determine mechanisms by which YWHAZ forms a complex with beta-catenin to promote cell proliferation and migration and inhibut apoptosis. In Specific Aim 2 we will focus on xenograft experiments in immunocompromised mice and the targeted delivery of miR mimics, inhibitors and siRNA in vivo to test the efficacy of using miR-based therapeutic approaches for endometriosis. These innovative studies will contribute to our understanding of the molecular mechanisms underlying the etiology of endometriosis and functionally link miR expression to target genes that are pathologically relevant.