MECHANISM OF MYCOBACTERIUM TUBERCULOSIS PERSISTENCE

在此输入文本，它是应用程序的新摘要信息。本节 文本长度不得超过30行。 M.结核病（Mtb）是全世界主要的死亡原因之一，每年夺去数百万人的生命。全球约有17亿人无症状地感染结核杆菌，这构成了全球公共卫生控制措施的主要障碍。先前的工作已经表明，在牛分枝杆菌中的主要σ因子RpoV的4.2结构域中的点突变（Arg His）是减毒的。感染MtbwhiB 3的小鼠显示出比感染野生型Mtb的小鼠显著更长的存活时间。此外，MtbwhiB 3感染小鼠的肺部似乎受到的不利影响要小得多。最近的研究表明，WhiB 3是一个4Fe-4S簇蛋白，并启动代谢的首选体内碳源，脂肪酸。我们假设WhiB 3是一个细胞内的氧化还原传感器，维持氧化还原稳态。为了更好地了解这种生理事件的机制，我们将确定有效的铁硫（Fe-S）重建所必需的WhiB 3氨基酸，并使用电子顺磁共振光谱（EPR）来表征这些突变的蛋白质。我们将使用全基因组表达谱来检查WhiB 3在维持氧化还原稳态中的贡献，并分析MtbwhiB 3的代谢产物谱。这些研究将把WhiB 3描述为干预的潜在靶点。伯明翰亚拉巴马大学（UAB）是亚拉巴马最大的雇主，在大学和卫生系统拥有18，000多名教职员工，并负责大学和社区内的52，900个全职等效工作。伯明翰地区每100个工作岗位中有8个，亚拉巴马每100个工作岗位中有2.8个与UAB有关。UAB在伯明翰都会区的整体经济影响每年超过30亿美元。与ARRA的目标一致，该应用程序将创造或保留约7个工作岗位。 515

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