cAMP signaling pathways within Mycobacterium tuberculosis

结核分枝杆菌内的 cAMP 信号通路

基本信息

批准号：
9089816
负责人：
Kathleen A McDonough
金额：
$ 36.09万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089816
关键词：
Address Adenylate Cyclase Affect Animal Model Antitubercular Agents Bacteria Binding Binding Sites Biological Markers Biology Camping Catabolism Cells Citric Acid Cycle Complex Cues Cyclic AMP Cyclic AMP Receptor Protein Diagnostic Disease ELF3 gene Environment Enzymes Family Gene Expression Gene Expression Regulation Genes Goals Granuloma Health Human Hypoxia Infection Intervention Intoxication Knock-out Metabolic Metabolic Pathway Metabolism Modeling Molecular Molecular Genetics Mus Mutate Mycobacterium tuberculosis Nature Necrosis Operon Pathogenesis Play Propionates Proteins Regulation Regulator Genes Regulon Reporter Reporter Genes Role Second Messenger Systems Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Staging Starvation Succinate Dehydrogenase Systems Biology Therapeutic Tuberculosis Virulence Work chromatin immunoprecipitation deep sequencing genetic approach global health improved insight macrophage microbial mouse model mutant new therapeutic target pathogen promoter response second messenger specific biomarkers tool transcription factor tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to negatively impact human health on a global scale. The long term goal of this project is to understand the means by which Mtb senses and responds to its host environment during infection, so that improved biomarkers and treatments for TB disease can be developed. Cyclic AMP (cAMP), which is generated from ATP by adenylyl cyclases, is a universal second messenger used by both microbial pathogens and their mammalian hosts to sense and respond to environmental cues. cAMP plays a central role in virulence gene regulation in Mtb and other bacterial pathogens through its allosteric interactions with cAMP receptor protein (CRP)-like transcription factors. Mtb encodes two such transcription factors: CrpMt, which contributes to virulence in a murine model; and Cmr, which regulates Mtb gene expression within macrophages. Previous work has shown that levels of cAMP within Mtb bacteria increase dramatically upon bacterial entry into macrophages, suggesting a role for cAMP in sensing and responding to the intra-macrophage environment. The current project addresses the hypothesis that cAMP signaling contributes to Mtb-host interactions by regulating gene expression within the bacterium in response to environmental conditions. This hypothesis will be addressed in three specific aims. Aim 1 will redefine the CrpMt regulon and its role in Mtb biology during infection at the global, cellular and molecular levels. Aim 2 addresses the role of Cmr in Mtb biology with a focus on its role in regulating propionate metabolism during macrophage infection and within granulomas. Aim 3 addresses the roles of CrpMt and Cmr as co-regulators with other transcription factors, of the espA virulence operon using a combination of molecular, genetic and cellular approaches. Completion of these studies will significantly advance understanding of cAMP's role in Mtb biology, particularly in the context of bacterial sensing and response to host-associated conditions. This information will contribute to the identification of stage-specific biomarkers of infection and new drug targets. The significance of this project is further enhanced by cAMP's established role in regulating virulence in a wide range of important bacterial pathogens, as well as the exceptionally large and unusual network of cAMP-associated signaling proteins in Mtb.

描述（由申请人提供）：结核分枝杆菌（MTB），结核病的病因（TB），在全球范围内继续对人类健康产生负面影响。该项目的长期目标是了解MTB感官并在感染过程中对其宿主环境做出反应的手段，以便可以开发出改善的结核病疾病的生物标志物和治疗方法。由ADENYLYL循环酶从ATP生成的环状AMP（CAMP）是微生物病原体及其哺乳动物宿主使用的通用第二信使，以感知并响应环境提示。 CAMP通过其与CAMP受体蛋白（CRP）样转录因子的变构相互作用在MTB和其他细菌病原体中的毒力基因调节中起着核心作用。 MTB编码两个这样的转录因子：CRPMT，这有助于鼠模型中的毒力；和CMR，它调节巨噬细胞中MTB基因的表达。先前的工作表明，在细菌进入巨噬细胞时，MTB细菌内的cAMP水平急剧增加，这表明cAMP在感应和应对巨噬细胞内环境中的作用。当前的项目解决了以下假设：cAMP信号传导通过调节细菌内基因表达对环境条件的响应，从而有助于MTB-HOST相互作用。该假设将以三个具体目标解决。 AIM 1将重新定义CRPMT Regulon及其在MTB中的作用在全球，细胞和分子水平上感染期间的生物学。 AIM 2解决了CMR在MTB生物学中的作用，其重点是其在调节巨噬细胞感染和肉芽肿内的丙酸代谢中的作用。 AIM 3使用分子，遗传和细胞方法的组合，解决了CRPMT和CMR作为与其他转录因子的共同调节剂的作用。这些研究的完成将大大提高人们对CAMP在MTB生物学中的作用的了解，尤其是在细菌感应和对宿主相关条件的反应的背景下。该信息将有助于鉴定特定于阶段的感染和新药物靶标。 CAMP在调节广泛的重要细菌病原体中的毒力以及MTB中与CAMP相关的信号蛋白的异常大且异常的网络中，CAMP在调节毒力中的确定作用进一步增强了该项目的重要性。