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: 10688066
• 负责人: Devan Jaganath
• 金额: $ 15.8万
• 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/10688066
• 关键词: Address; Adult; Age; Bioinformatics; Biological Assay; Biological Markers; Blood; California; Cessation of life; Child; Child Care; Childhood; Clinical; Consensus; Coupling; Data; Dedications; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Enrollment; Environment; Evaluation; Funding; Gene Expression; Gene Expression Profile; Goals; Health system; Hospital Referrals; Human; Immune response; Immunoassay; Infection; Infrastructure; International; 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; Reproducibility; Research; Research Personnel; Resources; Role; Sampling; San Francisco; Scientist; Shotguns; Site; Specificity; Sputum; Testing; Training; Translating; Triage; Tuberculosis; Tuberculosis diagnosis; Uganda; United States National Institutes of Health; Universities; Urine; Work; accurate diagnosis; biomarker discovery; biomarker panel; biomarker validation; 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 (TB) 是全世界儿童死亡的主要原因。痰液获取困难且痰量低 痰细菌载量是诊断的主要障碍，并且需要开发非痰、 基于生物标志物的儿童胸内结核病检测。儿童结核病宿主生物标志物的发现 需要更加关注下游蛋白质及其翻译后修饰 (PTM) 可能特定于疾病表型，并且可以更容易地转化为即时检测。随着 为了支持这项 K23 奖项，Devan Jaganath 博士将鉴定尿液中的宿主蛋白质组生物特征，该生物特征可以 实现儿童肺结核分诊和/或诊断测试的目标准确性。为了完成这个 目标是，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研究中心拥有广泛的蛋白质组设施 加利福尼亚州、旧金山 (UCSF)。在目标 1 中，他将对以下尿液样本进行靶向质谱分析： 患有确诊结核病和疑似结核病的儿童，并检查 10 种宿主蛋白​​的丰度和泛素化情况，这些蛋白 先前有证据表明与结核分枝杆菌 (Mtb) 蛋白作为候选生物标志物存在特异性相互作用。瞄准 2，他将对尿液样本使用鸟枪质谱法来鉴定所有宿主蛋白及其 PTM 可以将结核病状态区分为新的生物标志物，并进行通路分析以确定具有以下特征的子集： 与 Mtb 发病机制的功能相关性。在目标 3 中，他将应用机器学习分析来识别 可以实现分类和/或诊断的目标准确度阈值的最小生物标志物组合 胸内结核病检测。然后，他将评估有前途的生物特征的性能 独立的、前瞻性注册的测试集。通过这种方法，Jaganath 博士寻求优化生物标志物 通过将前瞻性临床队列与有针对性和无针对性的研究相结合，发现儿童结核病诊断 高通量方法全面检查儿童非痰样本中的宿主生物标志物。 Jaganath 博士的职业目标是成为一名将非痰生物标志物转化为临床工具的医师科学家 可以改善对结核病儿童的护理。为了支持他的独立之路，拟议的工作将是 与专门的多学科指导团队合作并接受国际儿科结核生物标志物培训 研究、蛋白质组分析的生物信息学和机器学习。 UCSF 拥有优越的环境， 致力于为初级研究人员提供广泛的研究和职业发展资源，穆拉戈 乌干达国家转诊医院是儿科结核病研究领域的领导者，拥有完善的基础设施 用于持续登记和样本收集。研究结果将支持 NIH R01 申请来验证 与现有的非痰诊断相比，大型、多样化队列中的生物标志物和生物特征。因此， K23 奖将为 Jaganath 博士提供重要的指导、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研究者。

项目成果

Epidemiology of Culture-Negative Pulmonary Tuberculosis-Alameda County, 2010-2019.

培养阴性肺结核流行病学 - 阿拉米达县，2010-2019 年。

• DOI: 10.1097/phh.0000000000001715
• 发表时间: 2023
• 期刊: Journal of public health management and practice : JPHMP
• 作者: Chen,Jennie;Marusinec,Rachel;Brown,Robert;Shiau,Rita;Jaganath,Devan;Chitnis,AmitS
• 通讯作者: Chitnis,AmitS

Toward Comprehensive Plasma Proteomics by Orthogonal Protease Digestion.

• DOI: 10.1021/acs.jproteome.1c00357
• 发表时间: 2021-08-06
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Fossati A;Richards AL;Chen KH;Jaganath D;Cattamanchi A;Ernst JD;Swaney DL
• 通讯作者: Swaney DL

A narrative review of tuberculosis in the United States among persons aged 65 years and older.

• DOI: 10.1016/j.jctube.2022.100321
• 发表时间: 2022-08
• 期刊: JOURNAL OF CLINICAL TUBERCULOSIS AND OTHER MYCOBACTERIAL DISEASES
• 影响因子: 2
• 作者: Wu, Iris L.;Chitnis, Amit S.;Jaganath, Devan
• 通讯作者: Jaganath, Devan