Metabolic biomarkers and biosignatures for improved diagnosis of Lyme disease

总结 莱姆病（LD）是美国最常见的媒介传播疾病， 2009年约有38 000例确诊和可能病例。目前推荐的方法 诊断LD是一种基于血清学的两层测试，其区分活动性和既往活动性的能力有限。 感染，早期诊断LD，并且在实验室之间不标准化。这些限制可能导致 误解，并导致数百万的诊断测试（FDA批准和未批准）被 每年都有这种感染。因此，一种新的方法来改进诊断开发是至关重要的 到外地。应用小分子生物标志物“代谢组学”的全球评价， 用于监测癌症和代谢疾病的生物特征和生物标记物的发现已经表明， 巨大的承诺。虽然这项技术尚未广泛应用于传染病，但它是 认识到传染病的表现是基于生物化学的改变， 系统因此，正如现在其他感染所显示的那样，我们假设代谢组学提供了一个 创新的方法来识别LD的生物特征和生物标志物。R21/R33应用 建议，在头两年，阐明LD的多种基于代谢组的生物特征;启动 鉴定包含这些生物特征的产品;并建立阐明生物特征的工具。 伯氏疏螺旋体代谢组。成功完成这些初步研究和工具开发工作 将导致在第3-5年的努力，以资格的LD生物签名;完成分子鉴定的 生物特征产品;并提供对B的全面分析。伯氏菌代谢组这些 涵盖整个R21/R33计划的活动是在三个具体目标的框架内进行的：1）发展 并鉴定代谢生物特征，以区分活动性LD与外观相似的感染，并定义阶段 包括治愈的LD; 2）鉴定和验证代谢物的化学结构， LD的生物特征;和3）评估B的代谢谱。burgdorferi。年底的总体目标 五年内将有合格的LD生物签名，可以应用于临床实验室使用质量 光谱法或适用于多分析物小分子诊断的另一种分析技术。

Summary Lyme disease (LD) is the most commonly reported vector-borne disease in the United States with approximately 38,000 confirmed and probable cases in 2009. The currently recommended method for diagnosing LD is a two-tiered serology-based test that is limited in its ability to differentiate active from previous infection, diagnose early LD, and is not standardized among laboratories. These limitations can result in misinterpretations and have led to millions of diagnostic tests (FDA approved and non-approved) being performed each year for this infection. Thus, a fresh approach for improved diagnostic development is critical to the field. Studies applying the global evaluation of small molecule biomarkers, "metabolomics", for the discovery of biosignatures and biomarkers for monitoring cancers and metabolic diseases have shown tremendous promise. Although this technology has not been widely applied for infectious diseases, it is recognized that infectious diseases are manifested based on alterations to the biochemistry of a biological system. Thus, as is now being shown with other infections, we hypothesize that metabolomics offers an innovative approach for identification of biosignatures and biomarkers of LD. This R21/R33 application proposes to, in the first two years, elucidate multiple metabolome-based biosignatures of LD; initiate identification of products that comprise these biosignatures; and establish tools for the elucidation of the Borrelia burgdorferi metabolome. Successful completion of these initial studies and tool development efforts will lead to efforts in Years 3-5 to qualify the LD biosignatures; complete the molecular identification of the biosignature products; and provide a comprehensive analysis of the B. burgdorferi metabolome. These activities encompassing the entirety of the R21/R33 program are framed within three Specific Aims: 1) Develop and qualify metabolic biosignatures that differentiate active LD from look-alike infections, and define the stages of disease including cured LD; 2) Identify and validate the chemical structures of the metabolites that comprise the biosignatures of LD; and 3) Evaluate the metabolic profile of B. burgdorferi. The overall goal at the end of five years will be to have qualified LD biosignatures that can be applied in clinical laboratories using mass spectrometry or another analytical technique suitable for a multi-analyte small molecule diagnostic.