Bacterial Determinants of Treatment Response in Mycobacteria Tuberculosis

摘要：概述 快速分子诊断技术的最新发展有望给结核病带来革命性的变化 控制力。这种测试可以直接在痰或其他临床样本上进行， 也依赖于结核分枝杆菌(MTB)基因特征的快速检测 作为耐药相关突变。临床研究表明，它们表现出 比痰涂片镜检更好，可靠地识别对几种一线的耐药性 毒品。然而，这些工具有两个重要的局限性。首先，当前的平台 直接从临床样本中提取结核分枝杆菌DNA的能力有限。和 其次，我们对穷人的遗传决定因素的了解存在重大差距 治疗反应。在这里，我们建议通过多项- 学科合作强调发现新的耐药生物标记物 和耐受性，确定最优的临床抽样策略 结核分枝杆菌DNA的快速检测及敏感微阵列的建立 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，并阻止疾病的进一步传播。的直接目标是 这些项目是为了1)发现和表征结核病耐药性的新生物标记物 通过人体研究和通过对引进的同基因菌株进行表型鉴定 突变；2)继续开发用于检测的新诊断方法的后期阶段 MTB DR，3)开发最有希望的临床采样策略，用于检测 来自结核分枝杆菌的DNA和4)开发和优化基于近护理点的微阵列 诊断设计用于检测成人和儿童结核分枝杆菌及其耐药性突变。

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.