Bacterial Determinants of Treatment Response in Mycobacteria Tuberculosis

结核分枝杆菌治疗反应的细菌决定因素

• 批准号: 10390297
• 负责人: MEGAN B MURRAY
• 金额: $ 297.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-18 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390297
• 关键词: Address; Adult; Antibiotic Resistance; Bacillus; Biological Markers; Cause of Death; Childhood; Clinical; Clinical Research; Communicable Diseases; DNA; Detection; Development; Diagnosis; Diagnostic; Disease; Drug Controls; Drug Tolerance; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Early Diagnosis; Early treatment; Failure; Genetic Determinism; Goals; Growth; Human; In Vitro; Interdisciplinary Study; Knowledge; Lead; Microscopy; Mutation; Mycobacterium tuberculosis; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Rapid diagnostics; Regimen; Resistance; Sampling; Sputum; Testing; Tuberculosis; Tuberculosis diagnosis; World Health Organization; base; curative treatments; design; diagnostic strategy; diagnostic tool; disease transmission; effective therapy; genetic signature; improved; molecular diagnostics; novel diagnostics; novel marker; point-of-care diagnostics; prevent; programs; rapid detection; resistance mutation; resistant strain; stem; tool; treatment response; tuberculosis diagnostics

Summary: Overview The recent development of rapid molecular diagnostics promises to revolutionize TB control. Such tests can be performed directly on sputum or other clinical samples and rely on the rapid detection of Mycobacteria tuberculosis (MTB) genetic signatures as well as drug resistance- associated mutations. Clinical studies demonstrate that they perform better than sputum smear microscopy and reliably identify resistance to several first line drugs. However, these tools suffer from two important limitations. First, current platforms are limited in their ability to extract MTB DNA directly from clinical samples. And secondly, there are major gaps in our knowledge of the genetic determinants of poor treatment responses. Here, we propose to address these gaps through a multi- disciplinary collaboration emphasizing discovery of new biomarkers of drug resistance and tolerance, the identification of optimal clinical sampling strategies directed toward detection of MTB DNA and the development of a sensitive micro-array based rapid diagnostic. Our long-term goal is to develop a diagnostic strategy that will improve the diagnosis of DR TB and stem the further spread of the disease. The immediate aims of this projects are to 1) discover and characterize novel biomarkers of TB drug resistance both through human studies and by phenotyping isogenic strains with introduced mutations; 2) continue late stage development of a novel diagnostic with which to detect MTB DR, 3) develop the most promising clinical sampling strategies with which to detect DNA from MTB and 4) develop and optimize a micro-array based near Point of Care diagnostic designed to detect adult and pediatric MTB and its drug resistance mutations.

摘要：概述 快速分子诊断的最新发展有望彻底改变结核病 控制。此类测试可以直接对痰液或其他临床样本进行 还依赖于结核分枝杆菌 (MTB) 基因特征的快速检测 作为与耐药性相关的突变。临床研究表明它们的表现 优于痰涂片镜检，并可靠地识别对几种一线药物的耐药性 药物。然而，这些工具有两个重要的限制。一、现有平台 直接从临床样本中提取 MTB DNA 的能力有限。和 其次，我们对贫困的遗传决定因素的认识存在重大差距。 治疗反应。在此，我们建议通过多种方式解决这些差距 学科合作强调发现新的耐药生物标志物 和耐受性，确定最佳临床采样策略 MTB DNA 检测和基于灵敏微阵列的快速检测的开发 诊断。我们的长期目标是开发一种诊断策略，以改善 诊断耐药结核病并阻止该疾病的进一步传播。近期目标 该项目的目的是 1) 发现并表征结核病耐药性的新型生物标志物 通过人体研究和引入引入的同基因菌株表型 突变； 2) 继续后期开发用于检测的新型诊断方法 MTB DR，3) 开发最有前途的临床采样策略来检测 来自 MTB 的 DNA 和 4) 开发和优化基于护理点附近的微阵列 旨在检测成人和儿童 MTB 及其耐药突变的诊断。