Antibody Reprtoire Characterization in Celiac Disease

描述（由申请人提供）：提议的努力旨在改变基于抗体生物标志物的医学诊断范例，使使用单一廉价的测试能够诊断数百种流行疾病和病症。虽然抗体目前是几种疾病的优秀生物标志物，但在一次测试中很少有超过几种抗体特异性的评估。此外，目前大多数测量抗体生物标志物的测试在单独使用时通常不能提供足够的诊断敏感性和特异性。为了解决这些问题，广泛的循环抗体库的特异性将同时进行分析，使用基于活试剂的新型集成发现和阵列构建过程。为了证明这种方法的内在力量和潜在的广泛适用性，我们将生成并临床验证可扩展抗体库谱分析微阵列在乳糜泻诊断、预测和治疗监测中的效用。利用高分辨率抗体特异性数据，新的自身和非自身抗原将被确定为可能参与疾病发病或进展的血清抗体的靶标。将抗体检测试剂发现过程应用于来自多个国家中心的大量疾病队列，将建立人类抗体特异性库数据库，为更好地了解乳糜泻等疾病的病因和个性化治疗提供广泛适用的工具。这一努力的成功将减少诊断测试的费用以及未确诊和误诊疾病的经济负担。

DESCRIPTION (provided by applicant): The proposed effort aims to change the paradigm of medical diagnostics based upon antibody biomarkers, enabling diagnosis of hundreds of prevalent diseases and conditions using a single inexpensive test. Although antibodies presently serve as excellent biomarkers for several diseases, seldom are more than a few antibody specificities assessed in a single test. Furthermore, most current tests that measure antibody biomarkers typically do not provide sufficient diagnostic sensitivity and specificity when used alone. To address these problems, the specificities of a broad spectrum of the circulating antibody repertoire will be profiled simultaneously, using a novel integrated discovery and array construction process based upon living reagents. To demonstrate the intrinsic power and potential broad applicability of this approach, we will generate and clinically validate the utility of expandable antibody repertoire profiling microarrays for diagnosis, prognostication, and therapeutic monitoring of Celiac Disease. Using high-resolution antibody specificity data, novel self- and non-self antigens will be identified as the targets of serum antibodies that may be involved in disease onset or progression. Application of the antibody detection reagent discovery process to a large number of disease cohorts from multiple national centers will enable establishment of the human antibody specificity repertoire database, providing a broadly applicable tool to better understand disease etiology and personalize therapy for Celiac and other diseases. Success of this effort will reduce the cost of diagnostic tests and the economic burden of undiagnosed and misdiagnosed disease. PUBLIC HEALTH RELEVANCE: The objective of the proposed project is to develop a general and scalable methodology to rapidly and economically profile the specificities of the repertoire of patient antibodies in a massively parallel format to diagnose disease. This new technology will first be applied to develop a improve diagnosis, early detection of Celiac Disease as well as to enable risk prognostication and therapeutic monitoring of patients. The method could then be directly extended to create low-cost diagnostic tools for a broad range of diseases for which current diagnostic technology is lacking. )