Using EV-microRNAs to identify a non-invasive biomarker of uterine fibroid outcomes

项目摘要 子宫平滑肌瘤（纤维瘤）是一种毁灭性的疾病，数百万妇女，谁的经验，发病率从 严重出血、盆腔疼痛或生殖问题。他们不成比例地影响黑人妇女在 美国的在确定子宫肌瘤的危险因素和非手术治疗方面进展缓慢。一 原因是依赖于超声诊断和监测，这是高度依赖于操作者， 在多发性纤维瘤的妇女中准确性差，并且不能提供关于肿瘤的分子信息。我们 这项研究将解决识别敏感、特异、机制性生物标志物的迫切需要， 通过非侵入性手段评估纤维瘤的存在、进展和未来生长的潜力。我们将 专注于microRNAs（miRNAs），在纤维瘤细胞中高度表达的非编码RNA， 参与通过分析包装在细胞外基质中的microRNA来驱动纤维瘤发展的机制， 囊泡（EV-miRNA）。循环EV-miRNA可以在血浆中非侵入性地测量，并且具有独特的生物学特性。 这些特性使其适合于研究和临床环境中的液体活检应用。长期 这项研究的目的是确定非侵入性的生物标志物，可以预测纤维瘤的生长和进展。的 本研究的目的是鉴定与纤维瘤存在相关的EV-miRNAs，并表征其特征。 与不同种族人群中疾病负担的临床指标相关。我们的核心假设是 EV miRNAs的特定模式将是纤维瘤存在和疾病的有效机制生物标志物， 负担这一假设是基于强有力的初步数据制定的，并将通过2个特定的 目标。在目的1中，我们提出建立血浆中EV-miRNA标签与 使用来自50名接受子宫切除术治疗肌瘤的妇女和50名对照者的数据， 因盆腔疼痛或大出血而进行子宫切除术，但无肌瘤。在目标2中，我们建议描述 血浆EV-miRNA表达与疾病负荷的相关性，通过肌瘤大小和月经量测量 出血严重程度，在50名接受子宫切除术治疗子宫肌瘤的女性（来自目标1的病例）和100名 新发现肌瘤的妇女，通常症状不太严重，肌瘤较小。的 我们的建议的创新方面包括：EV-miRNAs在纤维瘤中的研究，多学科研究， 团队，整体方法，以及液体活检工具的开发。我们建议的研究是回应 NICHD妇科健康与疾病分支的研究重点，促进发展， 子宫肌瘤和其他妇科疾病的新型生物标志物。这一贡献意义重大，因为它将 推进肌瘤病因学研究，通过重复， 机械生物标志物测量。我们提出的研究的预期结果有可能 改变纤维瘤研究和临床护理，并可能促进个性化治疗的发展。这些 这些进展将减少肌瘤的公共卫生负担，并改善少数群体的健康。

Project Summary Uterine leiomyomas (fibroids) are a devastating disorder for millions of women, who experience morbidity from heavy bleeding, pelvic pain, or reproductive problems. They disproportionately impact Black women in the United States. Progress in identifying risk factors and nonsurgical treatment for fibroids has been slow. One reason is reliance on ultrasonography for diagnosis and monitoring, which is highly operator dependent, has poor accuracy in women with multiple fibroids, and provides no molecular information about tumor(s). Our study will address the critical need to identify sensitive, and specific, mechanistic biomarkers that can help assess fibroid presence, progression, and potential for future growth through non-invasive means. We will focus on microRNAs (miRNAs), non-coding RNAs that are highly expressed in fibroid tumor cells and participate in mechanisms that drive fibroid development by profiling microRNAs packaged in extracellular vesicles (EV-miRNAs). Circulating EV-miRNAs can be measured non-invasively in plasma and have unique properties that make them suitable for liquid biopsy applications in research and clinical settings. The long-term goal of this research is to identify non-invasive biomarkers that can predict fibroid growth and progression. The objective of the proposed study is to identify EV-miRNAs related to fibroid presence and characterize their association with clinical measures of disease burden in a racially diverse population. Our central hypothesis is that a specific pattern of EV miRNAs will be a valid, mechanistic biomarker of fibroid presence and disease burden. This hypothesis was developed based on strong preliminary data and will be tested through 2 specific aims. In Aim 1, we propose to establish the relationship between EV-miRNA signatures in plasma and presence of fibroids using data from 50 women having a hysterectomy for fibroid treatment and 50 controls having a hysterectomy for pelvic pain or heavy bleeding with no fibroids. In Aim 2, we propose to characterize the association of plasma EV-miRNA expression and disease burden, measured by fibroid size and menstrual bleeding severity, among 50 women having a hysterectomy for fibroid treatment (cases from Aim 1) and 100 women with newly detected fibroids, who typically have less severe symptoms and smaller fibroids. The innovative aspects of our proposal include: the study of EV-miRNAs in fibroids, the multidisciplinary study team, the overall approach, and the development of liquid biopsy tools. Our proposed study is responsive to the research priorities of NICHD Gynecologic Health and Disease Branch, which promote the development of novel biomarkers for fibroids and other gynecologic disorders. This contribution is significant because it will advance fibroid etiologic research by enabling large, prospective studies of fibroid outcomes with repeated, mechanistic biomarker measurements. The anticipated outcomes of our proposed study have the potential to transform fibroid research and clinical care and may catalyze development of individualized treatments. These advancements will decrease the public health burden of fibroids and improve minority health.