Bacterial Determinants of Treatment Response in Mycobacteria Tuberculosis

摘要：概述 快速分子诊断的最新发展有望彻底改变结核病 控制这种测试可以直接对痰液或其他临床样品进行， 也依赖于结核分枝杆菌（MTB）基因特征的快速检测 与耐药性相关的突变。临床研究表明， 优于痰涂片镜检，可靠地鉴定对几种一线耐药 毒品然而，这些工具受到两个重要限制。第一，现有平台 直接从临床样品中提取MTB DNA的能力有限。和 第二，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。在这里，我们建议通过多方面的措施来解决这些差距， 强调发现新的耐药性生物标志物的学科合作 和耐受性，确定最佳临床采样策略， 结核分枝杆菌DNA的检测和基于敏感微阵列的快速检测技术的开发 诊断我们的长期目标是开发一种诊断策略， 诊断DR TB并阻止疾病的进一步传播。的近期目标 该项目的目标是：1）发现和表征结核病耐药性的新生物标志物 通过人类研究和通过对引入的 突变; 2）继续开发一种新的诊断方法， MTB DR，3）开发最有前途的临床采样策略，用于检测 来自MTB的DNA，以及4）开发和优化基于护理点附近的微阵列 用于检测成人和儿童结核分枝杆菌及其耐药突变的诊断。

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.