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: 9001351
• 负责人: Warren B Nothnick
• 金额: $ 31.66万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001351
• 关键词: Adverse effects; Affect; Age; Cell Proliferation; Cells; Chronic Disease; Clinical; Data; Development; Diagnosis; Diagnostic; Disease; 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; 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; diagnostic biomarker; endometriosis; improved; insight; mouse model; novel; paracrine; reproductive; restoration; therapeutic miRNA; 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（由申请人提供）：子宫内膜异位症是一种慢性疾病，其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。其高流行率的原因之一是，该疾病通常只有在发病后才被诊断出来。另一个临床缺陷是，该疾病的大多数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选择都是必要的。microRNAs已成为基因表达的关键转录后调控因子，是许多器官系统发育和功能的基础。最近的报道表明，mirna在子宫内膜异位症中表达错误。虽然这些报道为研究mirna在疾病病理生理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mirna在子宫内膜异位症的发展中发挥作用。为了填补这一知识空白，目前的应用将测试总体假设，即miR-451在子宫内膜异位症女性中表达显著降低，这种降低反过来通过增加细胞增殖和侵袭导致子宫内膜异位症植入物生长。我们进一步提出，基于这种错误表达，miR-451可能被证明是子宫内膜异位症的诊断标志物和/或治疗靶点。为了验证这一假设，我们将：1)证明miR-451在功能上决定了子宫内膜异位症植入物的生长，miRNA恢复治疗是一种有效的非甾体治疗方法；2)解剖miR-451调节子宫内膜异位症植入物生长所必需的关键靶点的分子机制；3)评估患有和不患有子宫内膜异位症的女性和狒狒的miR-451血清水平，以确定疾病的存在与miR-451水平之间是否存在相关性。因此，这一应用将为快速发展的mirna领域提供新的知识，并首次评估mirna在子宫内膜异位症病理生理中的功能作用。此外，这些研究将进行初步研究，以评估miR-451作为疾病诊断标志物的效用，并为基于mirna的新型子宫内膜异位症治疗方法的可能应用提供见解。这项研究的长期效益将增强我们对子宫内膜异位症的了解，并有可能改善妇女的健康。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。

项目成果

Dissecting the miR-451a-Mif Pathway in Endometriosis Pathophysiology Using a Syngeneic Mouse Model: Temporal Expression of Lesion Mif Receptors, Cd74 and Cxcr4.

• DOI: 10.3390/biomedicines10071699
• 发表时间: 2022-07-14
• 期刊: Biomedicines
• 影响因子: 4.7

Transgelin, a Novel Marker of Smooth Muscle Differentiation, Effectively Distinguishes Endometrial Stromal Tumors from Uterine Smooth Muscle Tumors.

Transgelin 是一种新型平滑肌分化标记物，可有效区分子宫内膜间质肿瘤和子宫平滑肌肿瘤。

• 发表时间: 2014
• 期刊: International journal of gynecological obstetrical and reproductive medicine research
• 作者: Tawfik,Ossama;Rao,Deepthi;Nothnick,WarrenB;Graham,Amanda;Mau,Brian;Fan,Fang
• 通讯作者: Fan,Fang

The Relationship and Expression of miR-451a, miR-25-3p and PTEN in Early Peritoneal Endometriotic Lesions and Their Modulation In Vitro.

• DOI: 10.3390/ijms23115862
• 发表时间: 2022-05-24
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Nothnick, Warren B.;Peterson, Riley;Minchella, Paige;Falcone, Tommaso;Graham, Amanda;Findley, Austin
• 通讯作者: Findley, Austin

Future Directions in Endometriosis Research and Therapeutics.

• DOI: 10.2174/1573404813666161221164810
• 发表时间: 2018-05
• 期刊: Current women's health reviews
• 作者: W. Nothnick;Courtney A. Marsh;Zahraa Alali

Circulating Micro-RNAs as Diagnostic Biomarkers for Endometriosis: Privation and Promise.

• DOI: 10.1016/j.jmig.2015.02.021
• 发表时间: 2015-07
• 期刊: JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY
• 影响因子: 4.1
• 作者: Nothnick, Warren B.;Al-Hendy, Ayman;Lue, John R.
• 通讯作者: Lue, John R.