Genetic, Metabolic and Regulatory Control of MIC and Relapse in M. tuberculosis

结核分枝杆菌 MIC 和复发的遗传、代谢和调控

• 批准号: 10584487
• 负责人: David Alland
• 金额: $ 81.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584487
• 关键词: Affect; Antitubercular Agents; Bacillus; Bacteria; Bacterial Physiology; Biological; Cell Death; Cells; Characteristics; Chemicals; Clinical; Computer Models; DNA Sequence Alteration; Data; Drug Tolerance; Drug resistance; Ethambutol; Event; Evolution; Future; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Health system; Intervention; Knowledge; Lead; Length; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Mutation; Mycobacterium tuberculosis; Network-based; Patient Noncompliance; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Prediction of Response to Therapy; Predisposition; Public Health; Radiology Specialty; Regimen; Regulator Genes; Regulatory Pathway; Relapse; Research; Rifampin; Surveys; System; Testing; Toxic effect; Treatment Failure; Treatment outcome; Tuberculosis; Variant; Work; biomarker development; candidate marker; causal variant; driving force; drug metabolism; drug relapse; drug sensitivity; fitness; functional genomics; gene network; gene regulatory network; genetic variant; genome-wide; global health; improved; improved outcome; in vivo; insight; isoniazid; knock-down; minimal inhibitory concentration; new therapeutic target; novel; personalized medicine; pressure; programs; rate of change; relapse patients; relapse risk; resistance gene; resistance mutation; response; success; tool; treatment duration; tuberculosis chemotherapy; tuberculosis drugs; tuberculosis treatment

ABSTRACT TB treatment is an enigma of ineffectiveness. Current TB chemotherapy rapidly kills nearly all bacteria within two weeks, yet tolerable treatment failure rates are only achieved after 6 months, and even then, ~5% of cases relapse. Our recent work shows that bacterial factors associated with small MIC shifts are important predictors of treatment outcome, but the driving forces behind those shifts are unknown. This project unites three labs, with highly complementary expertise, around interrogating carefully curated M. tuberculosis clinical isolates with leading edge approaches in genetics, metabolism, gene regulation and network-based modeling to reveal fundamental new knowledge about how TB responds to front-line drugs. The direct result of this effort will be a suite of candidate biomarkers with great potential to personalize treatment duration by predicting treatment outcome and greatly simplify TB drug trials, as well as novel drug targets to improve outcomes and shorten therapy. These translational aims will be pursued in future studies, using the insights, strains and tools developed in the program.

摘要 结核病治疗是一个无效的谜。目前的结核病化学疗法迅速杀死几乎所有的细菌内 两周后，可耐受的治疗失败率仅在6个月后达到，即使如此，约5%的病例 复发我们最近的工作表明，与小MIC变化相关的细菌因素是重要的预测因子 治疗结果，但这些变化背后的驱动力是未知的。这个项目联合了三个实验室， 与高度互补的专业知识，围绕审问精心策划的M。结核病临床分离株 利用遗传学、代谢、基因调控和基于网络的建模方面的前沿方法， 关于结核病如何对一线药物作出反应的基本新知识。这一努力的直接结果将是 一套候选生物标志物，具有通过预测治疗来个性化治疗持续时间的巨大潜力 结果和大大简化结核病药物试验，以及新的药物靶点，以改善结果和缩短 疗法这些翻译的目标将在未来的研究中追求，使用的见解，菌株和工具 在节目中发展。