High resolution plasma metabolomics to identify biomarkers of tuberculosis

项目摘要/摘要 结核病(TB)是一个巨大的全球公共卫生问题，也是由 世界范围内的传染病。缺乏与进展相关的已知生物标记物和生物途径 活动性结核病是发展护理点检测的主要障碍，而这一点是迫切需要的 需要在初级保健一级有效地诊断结核病，特别是在资源有限的国家。与 支持这项K23奖项的杰弗里·柯林斯，医学博士，公共卫生硕士，硕士将探索高分辨率代谢组学 可用于识别与活动性结核病和潜伏性结核病感染相关的新的代谢特征 (LTBI)具有发展为活动性结核病的高风险。他将利用由 NIAID资助的结核病研究单位(TBRU；U19 AI111211)，以确定宿主和分枝杆菌 在血浆中检测到的结核代谢产物可发展为活动性结核病的生物标志物(AIM 1)，宿主新陈代谢的变化是否可以识别患有LTBI的高危患者(目标2)，以及 在活动性结核病患者的尿液中是否可检测到结核分枝杆菌相关代谢物(目标3)。 这项研究试图确定活动性结核病和高危LTBI的新的分子特征，具有潜在的 转化为改进的诊断化验。这一研究策略将促进5年的职业发展 和培训计划，使柯林斯博士能够在统计计算和临床方面的背景基础上再接再厉 流行病学和获得关键的指导性研究培训。作为一名临床研究人员实现独立 具有独特的利基市场，利用系统生物学识别与结核病相关的新分子特征 为了获得对疾病病理生理学的新见解，柯林斯博士需要在以下方面进行进一步的培训：1)进行 前瞻性国际临床研究；2)代谢组学和生物标记物开发；3)数据 科学和生物信息学，重点是系统生物学。为了实现这些培训目标，柯林斯博士 组建了一个多学科导师团队，其中包括首席导师Henry Blumberg博士，他是 国际临床和转化性结核病研究(和TBRU Pi)和联合首席导师迪恩·琼斯博士 国际公认的代谢组学专家。他的共同导师是李淑昭博士，一位使用方面的专家 系统生物学描述宿主对传染性病原体的反应，研究员拉塞尔·肯普克博士 拥有结核病诊断评估方面的专业知识，以及著名的宿主监管专家Thomas Ziegler博士 新陈代谢。埃默里大学为此提供了卓越的智力和协作环境 研究。通过利用TBRU在埃塞俄比亚阿比斯阿比斯的广泛研究基础设施和独特的 在埃默里大学拥有高分辨率代谢组学和系统生物学方面的专业知识，柯林斯博士将 能够很好地执行拟议的研究目标和培训计划，并发展专业知识和 初步数据对NIH R01和其他使用多组学方法的资金具有竞争力，以更好地 了解和识别结核病的疾病谱。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is an enormous global public health problem and the leading cause of death due to an infectious disease worldwide. A lack of known biomarkers and biologic pathways associated with progression to active TB disease represents a major barrier to the development of point-of-care assays which are urgently needed to effectively diagnose TB at the primary care level, especially in resource-limited countries. With the support of this K23 award, Jeffrey Collins, MD, MPH, MSc, will explore whether high-resolution metabolomics can be used to identify novel metabolic signatures associated with active TB disease and latent TB infection (LTBI) with a high risk of progression to active TB. He will leverage unique clinical cohorts enrolled by the NIAID-funded TB Research Unit (TBRU; U19 AI111211) to determine whether host and Mycobacterium tuberculosis (Mtb) metabolites detected in plasma can be developed as biomarkers of active TB disease (Aim 1), whether changes in host metabolism can identify persons with LTBI at high risk of progression (Aim 2), and whether Mtb-associated metabolites are detectable in the urine of persons with active TB disease (Aim 3). This study seeks to identify novel molecular signatures of active TB and high-risk LTBI with potential for translation into improved diagnostic assays. This research strategy will facilitate a 5-year career development and training plan that will enable Dr. Collins to build on his background in statistical computing and clinical epidemiology and gain critical mentored research training. To achieve independence as a clinical investigator with a unique niche using systems biology to identify novel molecular signatures associated with TB disease and gain new insights into disease pathophysiology, Dr. Collins requires further training in: 1) conducting prospective international clinical research studies; 2) metabolomics and biomarker development; and 3) data science and bioinformatics with a focus on systems biology. To achieve these training aims, Dr. Collins has assembled a multidisciplinary mentorship team that includes lead mentor Dr. Henry Blumberg, an expert in international clinical and translational TB research (and TBRU PI) and co-lead mentor Dr. Dean Jones, an internationally recognized expert in metabolomics. His co-mentors are Dr. Shuzhao Li, an expert in using systems biology to describe the host response to infectious pathogens, Dr. Russell Kempker, an investigator with expertise in evaluation of TB diagnostics, and Dr. Thomas Ziegler, a renowned expert in regulation of host metabolism. Emory University provides an exceptional intellectual and collaborative environment for this research. By leveraging the extensive study infrastructure of the TBRU in Abbis Ababa, Ethiopia and unique expertise in high-resolution metabolomics and systems biology available at Emory University, Dr. Collins will be well positioned to carry out the proposed study aims and training plan and develop the expertise and preliminary data to be competitive for NIH R01 and other funding using multi-omics approaches to better understand and recognize the spectrum of TB disease.