Circulating MicroRNAs as Disease Biomarkers in Multiple Sclerosis

描述(由申请人提供)： 这项申请是对NIH FOA邀请申请项目的回应，该项目旨在识别和鉴定来自人体体液的基于细胞外RNA(ExRNA)的生物标记物，以诊断和监测疾病进展和治疗反应。我们建议在明确定义的多发性硬化症(MS)患者群体中识别和验证候选循环miroRNAs。NIH FOA强烈鼓励使用现有的人类生物样品集进行研究，对于UH2阶段，我们将利用名为CLORT(布里格姆和妇女医院多发性硬化症的综合纵向调查)的独特资源。SCRATE是12年前开始登记的2000多名多发性硬化症患者的队列，包括每年的血液样本、临床检查和定量MRI成像。我们提供的初步数据表明，我们确实可以在我们的多发性硬化症队列中测量循环中的miRNAs，并发现与疾病分期、治疗反应和残疾有关。对于UH3阶段，我们已经从学术和药物合作者那里确定了有价值的血液样本来源，这些样本将用于验证我们的UH2发现，并为在临床上使用循环miRNAs提供基础。UH2阶段的具体目标：1)通过将MS患者与健康对照组、其他神经疾病患者和其他自身免疫性疾病患者进行比较，确定将作为诊断生物标志物的miRNAs。2)通过比较RRMS患者、SPMS患者和PPMS患者，确定疾病分期的miRNA生物标志物。3)通过确定每个miRNA在两年内的变化并评估哪些miRNA对疾病状态的长期变化敏感来确定预后的miRNA生物标志物。4)通过比较治疗应答者和无应答者的基线miRNA表达，确定治疗反应miRNA生物标记物。5)通过将miRNAs与EDSS和MRI疾病状态的测量相关联来识别残疾miRNA生物标志物。UH3期的具体目标：将对UH2期确定的循环miRNAs进行广泛研究，我们将解决以下两个目标：1.在明确定义的独立患者队列中验证UH2期确定的miRNA生物标记物。2.确定在UH2期发现的哪些miRNAs可用作临床前疾病的生物标志物。我们将利用来自多个来源的特征良好的血清样本，包括：顶峰国际多发性硬化症联盟、NIH赞助的CombiRx临床试验、Biogen IDEC赞助的IMPACT试验、瑞典EIMS多发性硬化症流行病学调查、加拿大儿童脱髓鞘疾病研究和GEMS(基因与环境多发性硬化症研究)。

DESCRIPTION (provided by applicant): This application is in response to an NIH FOA inviting applications for projects to identify and qualify extracellular RNA (exRNA)-based biomarkers derived from human body fluids to diagnose and monitor disease progression and response to therapy. We propose to identify and validate candidate circulating miroRNAs in well-defined multiple sclerosis (MS) patient populations. Studies using existing human biospecimen collections were strongly encouraged by the NIH FOA and for the UH2 phase we will take advantage of a unique resource termed CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital). CLIMB is a cohort of over 2000 MS patients that began enrollment 12 years ago and includes yearly blood samples, clinical exams and quantitative MRI imaging. We present preliminary data that we can indeed measure circulating miRNAs in our MS cohort and have found links to disease stage, response to therapy and disability. For the UH3 phase we have identified valuable sources of blood samples from both academic and pharmaceutical collaborators that will be used to validate our UH2 findings and provide the basis for the use of circulating miRNAs in the clinic. SPECIFIC AIMS FOR UH2 PHASE: 1) Identify miRNAs that will act as diagnostic biomarkers by comparing MS patients to healthy controls, patients with other neurological diseases and patients with other autoimmune diseases. 2) Identify disease stage miRNA biomarkers by comparing RRMS patients, SPMS patients and PPMS patients. 3) Identify prognostic miRNA biomarkers by determining the change in each miRNA over two years and assessing which miRNAs are sensitive to long-term change in disease status. 4) Identify treatment response miRNA biomarkers by comparing the baseline miRNA expression in responders and non- responders to treatment. 5) Identify disability miRNA biomarkers by correlating miRNAs with EDSS and MRI measures of disease status. SPECIFIC AIMS FOR UH3 PHASE: Circulating miRNAs identified in the UH2 phase will be extensively studied and we will address the following two aims: 1. Validation of miRNA biomarkers identified in the UH2 phase in well defined independent patient cohorts. 2. Determine which miRNAs identified in the UH2 phase can be used as preclinical disease biomarkers. We will take advantage of well characterized serum samples from a number of sources including: The SUMMIT International MS Consortium, the NIH sponsored CombiRx clinical trial, the Biogen Idec sponsored IMPACT trial, the Swedish EIMS epidemiologic investigation of MS, the Canadian Pediatric Demyelinating Disease Study and the GEMS (Genes and Environment MS study).