Tuberculosis Pathogenesis and Drug Response

结核病发病机制和药物反应

基本信息

批准号：
9264398
负责人：
CHRISTOPHER M SASSETTI
金额：
$ 41.88万
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/9264398
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 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 Role Signal Transduction Site Stress Structure Transferase Triglycerides Tuberculosis Work base drug efficacy drug sensitivity effective therapy enzyme activity improved in vitro activity 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）：结核病的定义特征是临床潜伏期的长时间，在此期间，病因剂，结核分枝杆菌（MTB），如果有的话，生长缓慢。很难夸大这种静止行为的重要性，因为它类似于感染的慢性性质和抗生素的相对无效性。尽管越来越认识到静止是对压力的相对常见的微生物反应，但这些缓慢或非复制细胞的生理状态仍然神秘。为了研究静止的过渡，我们确定了在压力引起的停滞期间MTB生长停滞和长期存活所需的基因，以及伴随这种过渡的代谢改变所需的基因。基于这些互补研究，我们提出了一个调节性级联，该级联反应宿主衍生的压力，减慢细菌的生长并重塑长期停滞的代谢。在这个项目中，我们将结合高通量遗传和生化方法，以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，我们将表征适应静止所需的代谢改变，并确定在停滞期间生存所必需的哪一个。我们的目标是通过鉴定和表征维持静止状态所需的细胞途径来制定新策略，以加速结核病治疗。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis.

DOI：
10.1128/mbio.02133-16
发表时间：
2017-01-17
期刊：
mBio
影响因子：
6.4
作者：
DeJesus MA;Gerrick ER;Xu W;Park SW;Long JE;Boutte CC;Rubin EJ;Schnappinger D;Ehrt S;Fortune SM;Sassetti CM;Ioerger TR
通讯作者：
Ioerger TR

New TB treatments hiding in plain sight.

DOI：
10.15252/emmm.201404815
发表时间：
2015-02
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Olive AJ;Sassetti CM
通讯作者：
Sassetti CM

Relics of selection in the mycobacterial genome.

DOI：
10.1038/ng0610-476
发表时间：
2010-06
期刊：
Nature genetics
影响因子：
30.8
作者：
通讯作者：

Statistical analysis of genetic interactions in Tn-Seq data.

DOI：
10.1093/nar/gkx128
发表时间：
2017-06-20
期刊：
Nucleic acids research
影响因子：
14.9
作者：
DeJesus MA;Nambi S;Smith CM;Baker RE;Sassetti CM;Ioerger TR
通讯作者：
Ioerger TR

xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.

xCT 通过调节抗菌功能和炎症来增加结核病易感性

DOI：
10.18632/oncotarget.9052
发表时间：
2016-05-24
期刊：
Oncotarget
影响因子：
0
作者：
Cai Y;Yang Q;Liao M;Wang H;Zhang C;Nambi S;Wang W;Zhang M;Wu J;Deng G;Deng Q;Liu H;Zhou B;Jin Q;Feng CG;Sassetti CM;Wang F;Chen X
通讯作者：
Chen X