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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

基本信息

批准号：
10595535
负责人：
MEGAN B MURRAY
金额：
$ 291.67万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-18 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595535
关键词：
Address Adult Antibiotics 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 curative treatments design diagnostic strategy diagnostic tool disease transmission drug testing 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

项目摘要

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：概述最近发展的快速分子诊断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。