Metabolic biomarkers and biosignatures for improved diagnosis of Lyme disease

描述(由申请人提供)： 莱姆病(LD)是美国最常见的媒介传播疾病，2009年约有38,000例确诊病例和可能病例。目前推荐的诊断LD的方法是基于血清学的两级检测，这种方法在区分活动期和既往感染、诊断早期LD方面的能力有限，并且在实验室之间没有标准化。这些限制可能导致误解，并导致每年为这种感染进行数百万次诊断测试(FDA批准和非批准)。因此，改进诊断开发的新方法对该领域至关重要。应用小分子生物标记物的全球评估--“新陈代谢组学”--的研究，发现了用于监测癌症和代谢性疾病的生物特征和生物标记物，显示了巨大的前景。虽然这项技术尚未被广泛应用于传染病，但人们认识到，传染病是基于生物系统的生物化学变化而表现出来的。因此，正如现在对其他感染所显示的那样，我们假设代谢组学为识别LD的生物特征和生物标记物提供了一种创新的方法。该R21/R33应用程序建议，在头两年，阐明LD的多个基于代谢组的生物签名；启动组成这些生物签名的产品的鉴定；并建立工具来阐明伯氏疏螺旋体代谢组。这些初步研究和工具开发工作的成功完成将导致在3-5年内努力鉴定LD生物签名；完成分子鉴定 生物特征产品；并提供伯氏杆菌代谢组的全面分析。这些活动包括R21/R33计划的全部内容，其框架包括三个具体目标：1)开发和鉴定代谢生物特征，以区分活动性LD与外观相似的感染，并定义疾病的阶段，包括治愈的LD；2)鉴定和验证组成LD生物特征的代谢物的化学结构；以及3)评估伯氏杆菌的代谢特征。五年末的总体目标 年内将有合格的LD生物签名，可以应用于临床实验室，使用 质谱仪或其他适合于多分析物小分子诊断的分析技术。

DESCRIPTION (provided by applicant): 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.