Circulating MicroRNAs as Disease Biomarkers in Multiple Sclerosis

描述（由申请人提供）： 该申请是对NIH FOA邀请项目申请的回应，该项目旨在鉴定和鉴定源自人体体液的基于细胞外RNA（exRNA）的生物标志物，以诊断和监测疾病进展和对治疗的反应。我们建议在明确定义的多发性硬化症（MS）患者人群中识别和验证候选循环miroRNAs。NIH FOA强烈鼓励使用现有人类生物标本收集的研究，对于UH2阶段，我们将利用称为CLIMB（布里格姆妇女医院多发性硬化综合纵向调查）的独特资源。CLIMB是一个超过2000名MS患者的队列，12年前开始招募，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，我们确实可以测量MS队列中的循环miRNA，并发现了与疾病阶段，治疗反应和残疾的联系。对于UH3阶段，我们已经确定了来自学术和制药合作者的有价值的血液样本来源，这些血液样本将用于验证我们的UH2发现，并为临床中使用循环miRNA提供基础。UH2阶段的具体目标：1）通过将MS患者与健康对照、患有其他神经系统疾病的患者和患有其他自身免疫性疾病的患者进行比较来鉴定将充当诊断生物标志物的miRNA。2)通过比较RRMS患者、SPMS患者和PPMS患者来识别疾病阶段miRNA生物标志物。3)通过确定每种miRNA在两年内的变化来确定预后miRNA生物标志物，并评估哪些miRNA对疾病状态的长期变化敏感。4)通过比较治疗应答者和非应答者中的基线miRNA表达来鉴定治疗应答miRNA生物标志物。5)通过将miRNA与疾病状态的EDSS和MRI测量相关联来识别残疾miRNA生物标志物。UH3阶段的具体目标：将广泛研究UH2阶段鉴定的循环miRNA，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期鉴定的miRNA生物标志物。2.确定在UH2阶段鉴定的哪些miRNA可用作临床前疾病生物标志物。我们将利用来自多个来源的充分表征的血清样本，包括：SUMMIT International MS Consortium，NIH申办的CombiRx临床试验，Biogen Idec申办的IMPACT试验，瑞典EIMS MS流行病学调查，加拿大儿科脱髓鞘疾病研究和GEMS（基因和环境MS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).