Tuberculosis Pathogenesis and Drug Response

结核病发病机制和药物反应

基本信息

批准号：
8578516
负责人：
CHRISTOPHER M SASSETTI
金额：
$ 39.13万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578516
关键词：
Acetyl Coenzyme A Acetylation Adenylate Cyclase Affect Animals Antibiotic Therapy Antibiotics Behavior Biochemical Carbon Cell Death Cells Cessation of life Chemicals Chronic Clinical Cyclic AMP Disease Drug resistance Environment Enzymes Event Funding Generations Genes Genetic Goals Growth Homeostasis Hypoxia Immune In Vitro Individual Infection Link Lysine Maintenance Metabolic Metabolism Methods Modification Mutation Mycobacterium tuberculosis Nature Oxidation-Reduction Pathogenesis Pathway interactions Pharmaceutical Preparations Physiological Physiology Population Process Proteins Proteomics Regulation Regulatory Pathway Relative (related person)Role Signal Transduction Site Stress Structure Transferase Triglycerides Tuberculosis Work base drug efficacy drug sensitivity effective therapy enzyme activity improved in vivo latent infection metabolomics microbial mutant prevent programs public health relevance response treatment duration tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): The defining feature of tuberculosis is the long period of clinical latency during which the causative agent, Mycobacterium tuberculosis (Mtb), grows slowly if at all. It is difficult to overstate the importance of this quiescent behavior, as it likly underlies both the chronic nature of the infection and the relative ineffectiveness of antibiotics. Despite the growing recognition that quiescence is a relatively common microbial response to stress, the physiological state of these slowly- or non-replicating cells has remained enigmatic. To investigate the transition to quiescence, we identified both the genes required for the growth arrest and long-term survival of Mtb during stress-induced stasis, and the metabolic alterations that accompany this transition. Based on these complementary studies, we propose a regulatory cascade that senses host-derived stress, slows bacterial growth, and remodels metabolism for long-term stasis. In this project we will combine high-throughput genetic and biochemical methods to define the structure of this regulatory pathway and determine its ultimate role in promoting bacterial persistence and determining drug efficacy in vivo. We will then characterize the metabolic alterations that are required for the adaptation to quiescence and determine which of these are necessary for survival during stasis. Our goal is to devise new strategies to accelerate tuberculosis therapy through the identification and characterization of cellular pathways that are required for maintaining the quiescent state.

描述（由申请人提供）：结核病的显着特征是临床潜伏期较长，在此期间，病原体结核分枝杆菌（Mtb）生长缓慢（如果有的话）。这种静止行为的重要性怎么强调都不为过，因为它可能是感染的慢性性质和抗生素相对无效的基础。尽管人们越来越认识到静止是一种相对常见的微生物对压力的反应，但这些缓慢或不复制的细胞的生理状态仍然是个谜。为了研究向静止的转变，我们鉴定了在应激诱导的停滞期间结核分枝杆菌生长停滞和长期存活所需的基因，以及伴随这种转变的代谢改变。基于这些补充研究，我们提出了一个调控级联，可以感知宿主源性压力，减缓细菌生长，并重塑新陈代谢以实现长期停滞。在这个项目中，我们将结合高通量遗传和生化方法来定义该调节途径的结构，并确定其在促进细菌持久性和确定体内药物疗效中的最终作用。然后，我们将描述适应静止所需的代谢改变，并确定其中哪些对于停滞期间的生存是必需的。我们的目标是设计新的策略，通过识别和表征维持静止状态所需的细胞途径来加速结核病治疗。