Metabolic biomarkers and biosignatures for improved diagnosis of Lyme disease

用于改善莱姆病诊断的代谢生物标志物和生物特征

• 批准号: 8301968
• 负责人: John T Belisle
• 金额: $ 21.62万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301968
• 关键词: Amoxicillin; Antibiotics; Antigens; Bacteria; Biochemistry; Bioinformatics; Biological Assay; Biological Markers; Bite; Borrelia burgdorferi; Cancer Biology; Centers for Disease Control and Prevention (U.S.); Characteristics; Chemical Structure; Chronic; Clinical; Collaborations; Colorado; Communicable Diseases; Complex; Computer software; DNA; Data; Data Set; Deposition; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Doxycycline; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Etiology; Europe; Evaluation; Exanthema; FDA approved; Goals; Growth; Human; Individual; Infection; Laboratories; Lead; Logistic Regressions; Lyme Disease; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Diseases; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; New York; Order Spirochaetales; Patients; Phase; Phased Innovation Awards; Process; Qualifying; Reporting; Research; Resources; Sampling; Scientist; Serologic tests; Serum; Site; Source; Specificity; Staging; Standardization; Technical Expertise; Techniques; Technology; Testing; Ticks; United States; Universities; Urine; Vector-transmitted infectious disease; Visual; Western Blotting; base; biological systems; biosignature; comparative; disorder prevention; erythema migrans; improved; innovation; instrumentation; latent infection; medical schools; metabolomics; novel; novel diagnostics; pathogen; skin lesion; small molecule; tool; tool development; tuberculosis treatment

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.

描述（由申请人提供）： 莱姆病 (LD) 是美国最常报道的媒介传播疾病，2009 年约有 38,000 例确诊病例和疑似病例。目前推荐的 LD 诊断方法是基于两级血清学的检测，其能力有限用于区分活动性感染和既往感染、诊断早期 LD，并且实验室之间没有标准化。这些限制可能会导致误解，并导致每年针对这种感染进行数百万次诊断测试（FDA 批准和未经批准的）。因此，改进诊断开发的新方法对该领域至关重要。应用小分子生物标志物“代谢组学”的全球评估来发现生物特征和监测癌症和代谢疾病的生物标志物的研究显示出巨大的前景。尽管该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变化而表现出来的。因此，正如目前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方法。该 R21/R33 申请建议在头两年内阐明 LD 的多个基于代谢组的生物特征；开始识别包含这些生物特征的产品；并建立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将导致在第 3-5 年努力鉴定 LD 生物特征；完成分子鉴定 生物印记产品；并提供伯氏疏螺旋体代谢组的综合分析。这些涵盖整个 R21/R33 计划的活动被界定为三个具体目标： 1) 开发和鉴定代谢生物特征，以区分活动性 LD 和相似感染，并定义疾病的阶段，包括治愈 LD； 2) 鉴定并验证构成LD生物特征的代谢物的化学结构； 3) 评估伯氏疏螺旋体的代谢特征。五月底总体目标 几年后将拥有可用于临床实验室的合格 LD 生物特征 质谱法或其他适合多分析物小分子诊断的分析技术。 公共健康相关性：拟议的研究将确定莱姆病的新型小分子诊断生物标志物。诊断标记谱将包括人类宿主和病原体伯氏疏螺旋体的产物。这些将用于开发改进的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各个阶段并提供治愈测试。