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: 8236180
• 负责人: Warren B Nothnick
• 金额: $ 40.18万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236180
• 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. 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.

描述（由申请人提供）：子宫内膜异位症是一种子宫内膜组织异位生长的慢性疾病，其特点是骨盆疼痛和不孕，影响着全世界超过 7000 万女性。其高患病率的原因之一是该疾病通常只有在发病后才被诊断出来。另一个临床缺点是，该疾病的大多数治疗依赖于雌激素水平低下状态的诱导，这与不需要的副作用和对骨骼健康的负面影响有关。显然，需要更好的诊断工具和治疗选择。 microRNA 已成为基因表达的关键转录后调节因子，对于许多器官系统的发育和功能至关重要。最近的报告表明 miRNA 在子宫内膜异位症中表达错误。虽然这些报告为研究 miRNA 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性证据来证明 miRNA 在子宫内膜异位症发展中的作用。为了填补我们知识上的这一空白，当前的申请将测试总体假设，即患有子宫内膜异位症的女性中 miR-451 表达显着降低，这种降低反过来通过细胞增殖和侵袭的增加导致子宫内膜异位植入物的生长。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记物和/或治疗靶点。为了检验这一假设，我们将：1) 证明 miR-451 在功能上决定子宫内膜异位植入物的生长，并且 miRNA 恢复疗法是治疗该疾病的有效非类固醇方法，2) 剖析 miR-451 的分子机制调节对子宫内膜异位症植入物生长至关重要的关键靶标，3) 评估女性以及患有或不患有子宫内膜异位症的狒狒的 miR-451 血清水平，以确定是否存在子宫内膜异位症疾病的存在与 miR-451 水平之间的相关性。因此，该应用将为快速扩展的 miRNA 领域提供新知识，并首次评估 miRNA 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 作为该疾病诊断标记物的效用，并深入了解基于 miRNA 的新型疗法在子宫内膜异位症治疗中的可能应用。这项研究的长期好处将增强我们对子宫内膜异位症的了解，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。 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。了解该疾病如何发展并确定参与发病机制的因素可能会为该疾病提供新的治疗方法和诊断工具。