The Mycobacterium Tuberculosis Dormancy Program

结核分枝杆菌休眠计划

• 批准号: 7071645
• 负责人: MARTIN Inua VOSKUIL
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071645
• 关键词: Mycobacterium tuberculosis; bacterial genetics; enzyme activity; flow cytometry; genetic regulation; genetic regulatory element; guinea pigs; histopathology; immune response; laboratory mouse; latent bacterial disease; microorganism growth; microorganism metabolism; molecular cloning; nicotinamide adenine dinucleotide; nucleotide metabolism; oxidation reduction reaction; oxidative stress; pentosyltransferase; protein purification

DESCRIPTION (provided by applicant): A third of the world's population is infected with Mycobacterium tuberculosis (MTB) and most of these infections are in a latent state. Tubercle bacilli can remain inactive in lung lesions only to emerge decades later as new outbreaks of tuberculosis. Current therapy for tuberculosis often involves the administration of multiple antimicrobial agents over several months, probably because bacilli exist in a drug tolerant, dormant-like state in tubercle lesions. Understanding the physiology of bacilli during the latent infection phase is central to the goal of controlling and ultimately eradicating tuberculosis. We have demonstrated that as aerobic respiration is impeded (by reduced oxygen or by the presence of nitric oxide), bacilli strongly induce a co-regulated 48-gene genetic program called the "dormancy regulon". This regulon encodes a program required for adaptation to a long-term viable "dormant" or non-proliferating state. Bacillus survival during an anaerobic non-proliferating state requires conservation of energy, alternative mechanisms to maintain redox balance, and mechanisms to protect DNA and proteins. Our working hypothesis is: The dormancy regulon is a genetic program that confers survival to MTB during latency. To test this hypothesis we will investigate key aspects of dormant MTB that involve the role of dormancy regulon proteins in nucleotide and nucleic acid biology during dormancy. The research proposed herein is pivotal to understanding how the tubercle bacillus survives indefinitely during latent infection, and characterizes numerous candidate targets for drug development. This study compliments a collaboration with the Russian Research Center for Molecular Diagnostics and Therapy. A joint proposal will be submitted to the US Department of Health and Human Services Biotechnology Engagement Program that will address aspects of dormant MTB in human infection.

描述（由申请人提供）：世界三分之一的人口感染结核分枝杆菌（MTB），其中大多数感染都处于潜在状态。结核细菌在肺部病变中可能保持不活跃，直到几十年后出现，随着结核病的新暴发。目前对结核病的治疗通常涉及几个月内使用多种抗微生物剂，这可能是因为杆菌存在于结核病变中的药物耐受性，类似休眠状态的状态。了解潜在感染阶段的杆菌的生理学是控制和根除结核病的目标。我们已经证明，由于有氧呼吸受到阻碍（通过减少氧或一氧化氮的存在），杆菌强烈诱导了一个共同调节的48基因遗传程序，称为“休眠调节”。该规范编码适应长期可行的“休眠”或非增殖状态所需的程序。厌氧非增殖状态期间的芽孢杆菌生存需要能量保存，维持氧化还原平衡的替代机制以及保护DNA和蛋白质的机制。我们的工作假设是：休眠调节是一个遗传程序，在潜伏期期间赋予MTB生存。为了检验该假设，我们将研究休眠状态蛋白在休眠期间涉及休眠状态蛋白在核苷酸和核酸生物学中的作用的休眠MTB的关键方面。本文提出的研究是了解结节芽孢杆菌在潜在感染期间无限期生存的关键，并表征了许多用于药物开发的候选靶标。这项研究补充了与俄罗斯分子诊断和治疗研究中心的合作。联合提案将提交美国卫生与公共服务部生物技术参与计划，该计划将解决休眠MTB在人类感染中的各个方面。