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例确诊和可能病例。目前推荐的诊断LD的方法是一种基于血清学的两层测试，其区分活动性和既往感染的能力有限，诊断早期LD，并且在实验室之间没有标准化。这些限制可能导致误解，并导致每年对这种感染进行数百万次诊断测试（FDA批准和未批准）。因此，一种新的方法来改善诊断的发展是至关重要的领域。应用小分子生物标志物“代谢组学”的全球评价来发现用于监测癌症和代谢疾病的生物特征和生物标志物的研究已经显示出巨大的前景。虽然这项技术尚未广泛应用于传染病，但人们认识到，传染病是基于生物系统的生物化学改变而表现出来的。因此，正如现在其他感染所显示的那样，我们假设代谢组学为鉴定LD的生物特征和生物标志物提供了一种创新的方法。该R21/R33申请提出，在头两年，阐明LD的多种基于代谢组的生物特征;开始鉴定包含这些生物特征的产品;并建立用于阐明伯氏疏螺旋体代谢组的工具。成功完成这些初步研究和工具开发工作后，将在第3-5年对LD生物特征进行鉴定;完成分子鉴定 的生物特征产品;并提供一个全面的分析的B。伯氏菌代谢组涵盖整个R21/R33项目的这些活动在三个特定目标内进行：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）鉴定和验证构成LD生物特征的代谢物的化学结构; 3）评价B的代谢特征。burgdorferi。五年年底的总体目标 年将有合格的LD生物签名，可以应用于临床实验室， 质谱法或适用于多分析物小分子诊断的另一种分析技术。 公共卫生相关性：拟议的研究将确定莱姆病的新型小分子诊断生物标志物。诊断标志物谱将包括人类宿主和病原体伯氏疏螺旋体的产物。这些将用于开发用于改进莱姆病诊断测定的生物特征，这些测定不基于经典血清学，并且可以区分莱姆病的阶段并提供治愈测试。

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. PUBLIC HEALTH RELEVANCE: The proposed research will identify novel small molecule diagnostic biomarkers for Lyme disease. The diagnostic marker profile will include both products of the human host and the pathogen, Borrelia burgdorferi. These will be used to develop biosignatures for improved Lyme disease diagnostic assays that are not based on classical serology and that can differentiate between the stages of Lyme disease and provide a test of cure.