The Role of miR-451 in Endometriosis Pathophysiology and Treatment

描述(申请人提供)：子宫内膜异位症是一种慢性疾病，子宫内膜组织异位生长，以盆腔疼痛和不孕为特征，影响全球超过7000万妇女。其高患病率的原因之一是这种疾病通常只有在确诊后才被诊断出来。另一个临床缺点是，大多数疾病的治疗依赖于诱导低雌激素状态，这与不想要的副作用和对骨骼健康的负面影响有关。显然，更好的诊断工具和治疗方案都是有必要的。MicroRNAs已经成为基因表达的关键转录后调节因子，对许多器官系统的发育和功能至关重要。最近的报道表明，miRNAs在子宫内膜异位症中错误表达。虽然这些报告为研究miRNAs在疾病的病理生理学中的潜在作用奠定了初步的基础，但它们没有提供功能证据表明miRNAs在子宫内膜异位症的发展中发挥作用。为了填补我们知识中的这一空白，目前的应用将检验总体假设，即子宫内膜异位症患者miR-451的表达显著减少，这种减少反过来通过增加细胞增殖和侵袭导致子宫内膜异位植入物的生长。我们进一步提出，基于这种错误表达，miR-451可能被证明是一种有用的诊断标记和/或子宫内膜异位症的治疗靶点。为了验证这一假说，我们将：1)证明miR-451在功能上控制子宫内膜异位症植入物的生长，并且miRNA修复疗法是治疗该疾病的有效非类固醇方法；2)分析miR-451调控子宫内膜异位症植入物生长至关重要的关键靶点的分子机制；3)评估妇女以及患有和不患有子宫内膜异位症的狒狒血清miR-451水平，以确定疾病存在与miR-451水平之间是否存在相关性。因此，这一应用将为迅速扩大的miRNAs领域提供新的知识，并首次评估miRNAs在子宫内膜异位症病理生理学中的功能作用。此外，这些研究将进行初步研究，以评估miR-451作为该病诊断标记物的实用性，并为基于miRNA的新型疗法在子宫内膜异位症治疗中的可能应用提供洞察力。这项研究的长期益处将增进我们对子宫内膜异位症的了解，并有可能改善妇女的健康。这项拟议研究的结果有可能改变子宫内膜异位症的治疗和/或诊断方式。 公共卫生相关性：子宫内膜异位症是育龄妇女的一种重要疾病。了解疾病是如何发展的，并确定参与发病机制的那些因素，可能会为这种疾病提供新的治疗方法和诊断工具。

DESCRIPTION (provided by applicant): Endometriosis is a chronic disease in which endometrial tissue grows ectopically, is characterized by pelvic pain and infertility and affects over 70 million women world-wide. One of the reasons for its high prevalence is that the disease is usually diagnosed only after it has established. An additional clinical shortcoming is that the majority of treatments for the disease rely on the induction of a hypoestrogenic state which is associated with unwanted side effects and negative impacts on bone health. Clearly, both better diagnostic tools and treatment options are warranted. microRNAs have emerged as critical post-transcriptional regulators of gene expression that are fundamental for development and function of many organ systems. Recent reports have suggested that miRNAs are mis-expressed in endometriosis. While these reports have laid the initial groundwork to examine the potential role of miRNAs in the pathophysiology of the disease, they have provided no functional evidence demonstrating a role for miRNAs in the development of endometriosis. To fill this gap in our knowledge, the current application will test the overall hypothesis that miR-451 expression is significantly reduced in women with endometriosis and this reduction in turn leads to endometriotic implant growth via increases in cell proliferation and invasion. We further propose, based upon this mis-expression, that miR-451 may prove useful as a diagnostic marker and/or a therapeutic target for endometriosis. To test this hypothesis, we will: 1) demonstrate that miR-451 functionally dictates growth of endometriotic implants and that miRNA restoration therapy is an effective, non-steroidal approach to treating the disease, 2) dissect the molecular mechanisms by which miR-451 regulates key targets which are essential for endometriotic implant growth and 3) assess miR- 451 serum levels in women as well as baboons with and without endometriosis to determine if there is a correlation between presence of disease and levels of miR-451. As such, this application will provide new knowledge in the rapidly expanding field of miRNAs and provide the first assessment of a functional role of miRNAs in the pathophysiology of endometriosis. Further, these studies will conduct the initial studies to evaluate the utility of miR-451 as a diagnostic marker for the disease as well as provide insight into the possible application of novel, miRNA-based therapies for endometriosis treatment. The long-term benefits of this research will enhance our understanding on the disease endometriosis and has the potential to improve women's health. The outcomes from the proposed research have the potential to change the way endometriosis may be treated and/or diagnosed. PUBLIC HEALTH RELEVANCE: Endometriosis is a significant disease in women of reproductive age. Understanding how the disease develops and identifying those factors which participate in the pathogenesis may allow for new treatments and diagnostic tools for this disease.