The Role of miR-451 in Endometriosis Pathophysiology and Treatment

miR-451 在子宫内膜异位症病理生理学和治疗中的作用

• 批准号: 8800561
• 负责人: Warren B Nothnick
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800561
• 关键词: Adverse effects; Affect; Age; Cell Proliferation; Cells; Chronic Disease; Clinical; Data; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Disease model; Endometrial; Epithelial Cells; Event; Functional disorder; Gene Expression; Goals; Growth; High Prevalence; Implant; Infertility; Knowledge; MMP3 gene; Mediating; Menstrual cycle; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mus; Outcome; Papio; Pathogenesis; Pelvic Pain; Regulation; Regulator Genes; Replacement Therapy; Reporting; Repression; Research; Role; Serum; Staging; Stromal Cells; Testing; Therapeutic; Tissues; Translations; Woman; Women' s Health; autocrine; base; body system; bone health; endometriosis; improved; insight; mouse model; novel; paracrine; reproductive; restoration; therapeutic target; tool

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.

描述（申请人提供）：子宫内膜异位症是一种慢性疾病，其中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。其发病率高的原因之一是，这种疾病通常只有在确诊后才能被诊断出来。另一个临床缺点是，大多数疾病的治疗依赖于低雌激素状态的诱导，这与不必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必要的。 microRNA已经成为基因表达的关键转录后调节因子，其对于许多器官系统的发育和功能是基本的。最近的研究表明，miRNAs在子宫内膜异位症中存在错误表达。虽然这些报道为研究miRNAs在疾病病理生理学中的潜在作用奠定了初步基础，但它们没有提供功能证据证明miRNAs在子宫内膜异位症发展中的作用。为了填补我们知识中的这一空白，本申请将测试总体假设，即miR-451表达在患有子宫内膜异位症的女性中显著降低，并且这种降低反过来通过细胞增殖和侵袭的增加导致异位植入物生长。基于这种错误表达，我们进一步提出，miR-451可能被证明可用作子宫内膜异位症的诊断标志物和/或治疗靶点。为了验证这个假设，我们将：1）证明miR-451在功能上决定肿瘤植入物的生长，并且miRNA恢复疗法是治疗该疾病的有效的非甾体方法，2）剖析miR-451调节对肿瘤植入物生长至关重要的关键靶标的分子机制，3）评估miR-451对肿瘤植入物生长的影响。451血清水平在妇女以及狒狒与和没有子宫内膜异位症，以确定是否有疾病的存在和miR-451水平之间的相关性。因此，本申请将提供新的知识，在迅速扩大的领域的miRNA，并提供第一次评估的功能作用的miRNA在子宫内膜异位症的病理生理。此外，这些研究将进行初步研究，以评估miR-451作为疾病诊断标志物的实用性，并为基于miRNA的新型治疗方法在子宫内膜异位症治疗中的可能应用提供见解。这项研究的长期益处将提高我们对子宫内膜异位症疾病的认识，并有可能改善女性的健康。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。