MECHANISM OF MYCOBACTERIUM TUBERCULOSIS PERSISTENCE

结核分枝杆菌持续存在的机制

基本信息

批准号：
7652988
负责人：
ADRIE JC STEYN
金额：
$ 36.59万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7652988
关键词：
Affect Alabama Alleles Amino Acids Anabolism Area Attenuated Bacillus (bacterium)Biological Assay Biology Carbon Cause of Death Cells Communities DNA DNA Binding DNA Microarray Chip DNA-Binding Proteins Data Development Disease Electron Spin Resonance Spectroscopy Equilibrium Event Exposure to Faculty Fatty Acids Funding Genetic Goals Health system Homeostasis Human Hydroxyl Radical Hypoxia Immune response In Vitro Inflammatory Intervention Iron Knowledge Life Ligation Lipids Lung MMP3 gene Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Molecular Profiling Mus Mutagenesis Mutate Mycobacterium bovis Mycobacterium tuberculosis NADH NADP Occupations Oxidation-Reduction Oxidative Stress Physiological Point Mutation Process Production Property Protein Fragment Proteins Public Health Regulation Regulon Resistance Series Sigma Factor Signal Transduction Sirolimus Source Stress Sulfhydryl Compounds Sulfur System Technology Time Transcriptional Activation Translating Triglycerides Tuberculosis Universities Work base economic impact genetic regulatory protein genome-wide in vivo mutant mycobacterial novel novel therapeutic intervention oxidation prevent reconstitution response sensor sulfolipids

项目摘要

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. M. tuberculosis (Mtb) is one of the leading causes of death worldwide and claims millions of lives annually. Approximately ~1.7 billion people worldwide are asymptomatically infected with the tubercle bacillus and constitute a major impediment to worldwide public health control measures. Previous work had shown that a point mutation (Arg His) in the 4.2 domain of RpoV, the principal sigma factor in Mycobacterium bovis, is attenuating. Mice infected with MtbwhiB3 showed significantly longer survival times than mice infected with the wild type Mtb. In addition, the lungs of MtbwhiB3-infected mice appeared much less adversely affected. Recent studies have shown that WhiB3 is a 4Fe-4S cluster protein and initiates the metabolic switchover to the preferred in vivo carbon source, fatty acids. We hypothesize that WhiB3 is an intracellular redox sensor that maintains redox homeostasis. To better understand the mechanism of this physiological event, we will identify the WhiB3 amino acids necessary for effective iron-sulfur (Fe-S) reconstitution, and use electron paramagnetic resonance spectroscopy (EPR) to characterize these mutated proteins. We will use genome-wide expression profiling to examine the contribution of WhiB3 in maintaining redox homeostasis, and analyze the metabolite profile of MtbwhiB3. These studies will characterize WhiB3 as a potential target for interventions. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs within the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain ~7 jobs. 515

在此处输入文本，该文本是您的应用程序的新摘要信息。本节文本不得超过 30 行。结核分枝杆菌 (Mtb) 是全世界导致死亡的主要原因之一，每年夺去数百万人的生命。全球约有 17 亿人无症状感染结核杆菌，构成全球公共卫生控制措施的主要障碍。先前的研究表明，牛分枝杆菌的主要西格玛因子 RpoV 4.2 结构域中的点突变 (Arg His) 正在减弱。感染 MtbwhiB3 的小鼠表现出比感染野生型 Mtb 的小鼠显着更长的存活时间。此外，感染 MtbwhiB3 的小鼠肺部受到的不利影响似乎要小得多。最近的研究表明，WhiB3 是一种 4Fe-4S 簇蛋白，可启动代谢转换为首选的体内碳源脂肪酸。我们假设 WhiB3 是一种维持氧化还原稳态的细胞内氧化还原传感器。为了更好地了解这一生理事件的机制，我们将鉴定有效铁硫 (Fe-S) 重建所需的 WhiB3 氨基酸，并使用电子顺磁共振波谱 (EPR) 来表征这些突变蛋白。我们将使用全基因组表达谱来检查 WhiB3 在维持氧化还原稳态中的贡献，并分析 MtbwhiB3 的代谢谱。这些研究将 WhiB3 描述为潜在的干预目标。阿拉巴马大学伯明翰分校 (UAB) 是阿拉巴马州最大的雇主，在大学和卫生系统拥有超过 18,000 名教职员工，负责大学和社区内的 52,900 个全职同等工作岗位。伯明翰地区每 100 个工作岗位中有 8 个与阿拉巴马州每 100 个工作岗位有 2.8 个与 UAB 有关。 UAB 对伯明翰都市区的总体经济影响每年超过 30 亿美元。与 ARRA 目标一致，该应用程序将创造或保留约 7 个就业岗位。 515