Host Proteomic Biosignatures for a Urine-based Diagnosis of Pulmonary Tuberculosis in Children

用于基于尿液诊断儿童肺结核的宿主蛋白质组生物特征

• 批准号: 10248492
• 负责人: Devan Jaganath
• 金额: $ 21.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248492
• 关键词: Address; Adult; Age; Bioinformatics; Biological Assay; Biological Markers; Blood; California; Cessation of life; Child; Child Care; Childhood; Clinical; Consensus; Coupling; Data; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diagnostic tests; Disease; Enrollment; Environment; Evaluation; Funding; Gene Expression; Gene Expression Profile; Goals; Health system; Hospital Referrals; Human; Immune response; Immunoassay; Infection; Infrastructure; International; Lead; Machine Learning; Mass Spectrum Analysis; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Mycobacterium tuberculosis; Nested Case-Control Study; Pathogenesis; Pathway Analysis; Pathway interactions; Performance; Physicians; Post-Translational Protein Processing; Prospective cohort; Proteins; Proteome; Proteomics; Public Health; Pulmonary Tuberculosis; Reporting; Research; Research Personnel; Resources; Role; Sampling; San Francisco; Scientist; Shotguns; Site; Specificity; Sputum; Testing; Training; Translating; Triage; Tuberculosis; Uganda; United States National Institutes of Health; Universities; Urine; Work; accurate diagnosis; base; biomarker discovery; biomarker panel; biosignature; candidate marker; career; career development; cohort; disease phenotype; experience; improved; mortality; multidisciplinary; novel; novel marker; point of care; point of care testing; pre-clinical; prospective; protein biomarkers; research and development; sample collection; tool

PROJECT ABSTRACT Tuberculosis (TB) is a leading cause of mortality in children worldwide. Difficulty in obtaining sputum and a low sputum bacillary load are major barriers to diagnosis, and necessitate the development of a non-sputum, biomarker-based assay for childhood intrathoracic TB disease. Host biomarker discovery for childhood TB requires a greater focus on downstream proteins and their post-translational modifications (PTMs) that are more likely to be specific to a disease phenotype and can be more easily translated into a point-of-care test. With the support of this K23 award, Dr. Devan Jaganath will identify a host proteomic biosignature in urine that can achieve the goal accuracy for a triage and/or diagnostic test for pulmonary TB in children. To complete this objective, he will leverage an ongoing prospective cohort of symptomatic children being evaluated for intrathoracic TB in Kampala, Uganda, with the extensive proteomic facilities available at the University of California, San Francisco (UCSF). In Aim 1, he will perform targeted mass spectrometry on urine samples from children with confirmed vs. unlikely TB, and examine the abundance and ubiquitylation of 10 host proteins that have prior evidence of specific interactions with M. tuberculosis (Mtb) proteins as candidate biomarkers. In Aim 2, he will use shotgun mass spectrometry on the urine samples to identify all host proteins and their PTMs that can differentiate TB status as novel biomarkers, and perform pathway analysis to determine the subset with functional relevance to Mtb pathogenesis. In Aim 3, he will apply machine learning analyses to identify the smallest combination of biomarkers that can achieve the target accuracy thresholds for a triage and/or diagnostic test for intrathoracic TB disease. He will then evaluate the performance of promising biosignatures in an independent, prospectively enrolled test set. Through this approach, Dr. Jaganath seeks to optimize biomarker discovery for childhood TB diagnosis by coupling prospective clinical cohorts with a targeted and untargeted high-throughput approach to comprehensively examine non-sputum samples for host biomarkers for children. Dr. Jaganath's career goal is to be a physician scientist who translates non-sputum biomarkers into clinical tools that can improve the care of children with TB. To support his path to independence, the proposed work will be paired with a dedicated, multidisciplinary mentorship team and training in international pediatric TB biomarker studies, bioinformatics for proteomic analysis, and machine learning. UCSF is an outstanding environment that is committed to junior investigators with extensive resources for research and career development, and Mulago National Referral Hospital in Uganda is a leader in pediatric TB research, and has the established infrastructure for ongoing enrollment and sample collection. The findings will support an NIH R01 application to validate the biomarkers and biosignatures in large, diverse cohorts in comparison to existing non-sputum diagnostics. Thus, the K23 award will provide Dr. Jaganath with the critical mentorship, training, resources and experience to become an independent investigator who can make important contributions to the field of childhood TB.

项目摘要 结核病是全球儿童死亡的主要原因。取痰困难和低血压 痰细菌载量是诊断的主要障碍，并有必要发展为非痰， 基于生物标记物的儿童胸腔内结核病检测。儿童结核病宿主生物标记物的发现 需要更多地关注下游蛋白质及其翻译后修饰(PTM)，这些蛋白质 可能是特定于一种疾病表型的，可以更容易地转化为护理点测试。与 为了支持这项K23奖项，Devan Jaganath博士将在尿液中鉴定出一种宿主蛋白质组生物签名，它可以 达到对儿童肺结核进行分类和/或诊断测试的目标准确性。要完成这项工作 目标，他将利用正在进行的有症状儿童的前瞻性队列进行评估 乌干达坎帕拉的胸腔内结核病，拥有牛津大学广泛的蛋白质组学设施 加州，旧金山(加州大学旧金山分校)。在目标1中，他将对来自以下国家的尿样进行定向质谱分析 确诊与不太可能患有结核病的儿童，并检查10种宿主蛋白的丰度和泛素化 有与结核分枝杆菌(Mtb)蛋白作为候选生物标志物的特定相互作用的先前证据。在AIM 2，他将使用鸟枪质谱仪对尿样进行鉴定，以确定所有宿主蛋白及其PTM 可以将结核病状态作为新的生物标志物进行区分，并进行路径分析以确定亚组 与结核分枝杆菌发病机制相关的功能。在目标3中，他将应用机器学习分析来识别 能够达到分类和/或诊断的目标准确度阈值的最小生物标志物组合 胸腔内结核病检测。然后，他将评估有希望的生物签名在 独立的、预期注册的测试集。通过这种方法，Jaganath博士试图优化生物标记物 通过将前瞻性临床队列与定向和非定向研究相结合来发现儿童结核病诊断 高通量方法，全面检查儿童宿主生物标志物的非痰样本。 Jaganath博士的职业目标是成为一名内科科学家，将非痰生物标记物转化为临床工具 这可以改善对结核病儿童的护理。为了支持他走向独立的道路，拟议的工作将是 与国际儿科结核病生物标记物方面的专门、多学科指导团队和培训相结合 研究、用于蛋白质组分析的生物信息学和机器学习。加州大学旧金山分校是一个出色的环境 致力于初级调查人员，拥有广泛的研究和职业发展资源，而穆拉戈 乌干达国家转诊医院在儿科结核病研究方面处于领先地位，并拥有成熟的基础设施 用于正在进行的注册和样本收集。这些发现将支持NIH R01应用程序来验证 与现有的非痰诊断相比，在大的、多样化的队列中进行生物标志物和生物签名。因此， K23奖项将为Jaganath博士提供关键的指导、培训、资源和经验 成为一名能够为儿童结核病领域做出重要贡献的独立调查员。