IDENTIFICATION AND VALIDATION OF BIOMARKERS FOR VASCULITIS

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)：生物标记物的发现和验证，以及特定挑战主题03-OD(ORDR)-101*：验证罕见疾病的功能结果的生物标记物。系统性脉管炎是一组以严重的血管炎症为特征的疾病，导致动脉狭窄或闭塞，如果不治疗，器官损害或死亡。两种相关的血管炎，韦格纳肉芽肿病(WG)和显微镜下多血管炎(MPA)，每一种都与抗中性粒细胞胞浆抗体(ANCA)相关，并以危及器官和生命而闻名，在缓解期后容易复发。通过积极的免疫抑制治疗，这些ANCA相关血管炎(AAV)的大多数患者都能存活下来，但随后的病程多种多样，复发很常见，预计血管炎或其治疗会导致长期发病率。对疾病活动性、对治疗的反应性、复发风险和长期损害的标记物的需求严重不足。准确的标记将在早期发现耀斑以预防急性和慢性疾病、避免过度治疗以及在实践、早期概念验证治疗研究和更大规模的试验中衡量治疗反应方面大有裨益。现在有两项研究为加速AAV患者发现有用的生物标记物提供了前所未有的机会，这是因为它们已经建立了庞大的队列、全面的临床数据收集系统、与每次访问相关的生物标本储存库以及纵向性质：脉管炎临床研究联盟(VCRC)纵向研究和ANCA相关性脉管炎(RAVE)临床试验中的Rituximab。基础科学研究人员在合作中表达的兴趣证明了这些资料库的价值。计划对血小板活化、血管炎症和免疫学、内皮损伤和表位特异性ANCA亚群的生物标记物进行开创性研究。这些研究将确定和验证活动性脉管炎的标志物和预测未来病情或缓解的标志物。建议的工作与NIH通过2009年《美国复苏与再投资法案》提供资金的目标完全一致：进行这些研究所需的所有材料和专业知识都已准备就绪，可立即使用(“准备好铲”)，资金将快速有效地用于在美国学术医疗中心创造和保留就业机会。拟议的研究将确定血液中循环的生物标记物，对这些标记物的测量将有助于临床医生护理ANCA相关性脉管炎患者，这是一种罕见的严重血管炎症疾病。这些研究的结果也将在这些罕见但重要的疾病的未来临床试验的设计中发挥重要作用，并将为其他类型的脉管炎的生物标记物的开发提供洞察。 公共卫生相关性：拟议的研究将确定血液中循环的生物标记物，其测量将有助于临床医生护理ANCA相关性脉管炎患者，这是一组罕见的严重血管炎症疾病。这些研究的结果也将在这些罕见但重要的疾病的未来临床试验的设计中发挥重要作用，并将为其他类型的脉管炎的生物标记物的开发提供洞察。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03): Biomarker Discovery and Validation, and specific Challenge Topic 03-OD (ORDR)-101*: Validating Biomarkers for Functional Outcomes in Rare Diseases. The systemic vasculitides are a group of diseases characterized by severe inflammation of blood vessels leading to arterial stenosis or occlusion, and organ damage or death if untreated. Two related vasculitides, Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), each associated with anti-neutrophil cytoplasmic antibodies (ANCA) and notable for being organ- and life-threatening and prone to relapse after periods of remission. With aggressive immunosuppressive treatment, most patients with these ANCA- associated vasculitides (AAV) survive, but subsequent disease course is variable, relapse is common, and long-term morbidity from vasculitis or its treatment is expected. There is a significant unmet need for markers of disease activity, responsiveness to therapy, risk of relapse, and long-term damage. Accurate markers would be of great benefit in detecting flares early to prevent acute and chronic morbidities, avoiding over-treatment, and measuring response to treatment in practice, early-phase proof-of-concept treatment studies, and larger trials. Two studies now offer an unprecedented opportunity to accelerate discovery of useful biomarkers in patients with AAV, due to their large and already established cohorts, comprehensive clinical data collection systems, repositories of biological specimens linked to each visit, and longitudinal nature: the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, and the Rituximab in ANCA-Associated Vasculitis (RAVE) clinical trial. The value of these repositories is evidenced by the interest that basic science investigators have expressed in collaboration. Plans are presented for ground-breaking studies on biomarkers of platelet activation, vascular inflammation and immunology, endothelial damage, and epitope-specific ANCA subsets. These studies will identify and validate markers of active vasculitis and markers predictive of future flare or remission. The work proposed is fully consistent with the goals of NIH funding through the American Recovery and Reinvestment Act of 2009: All of the materials and expertise necessary to conduct these studies are ready and available for immediate use ("shovel ready") and the funds would be used quickly and efficiently to create and retain jobs in US academic medical centers. The proposed studies will identify biomarkers circulating in the blood, measurement of which will assist clinicians in the care of patients with ANCA-associated vasculitis, a set of rare, severe diseases of inflammation of blood vessels. Results of these studies will also be important in the design of future clinical trials in these rare but important diseases and will provide insight into biomarker development in other types of vasculitis. PUBLIC HEALTH RELEVANCE: The proposed studies will identify biomarkers circulating in the blood, measurement of which will assist clinicians in the care of patients with ANCA-associated vasculitis, a set of rare, severe diseases of inflammation of blood vessels. Results of these studies will also be important in the design of future clinical trials in these rare but important diseases and will provide insight into biomarker development in other types of vasculitis.