CELL TO CELL SIGNALING IN MYCOBACTERIA

分枝杆菌中的细胞间信号传导

• 批准号: 7491688
• 负责人: Moses Lutaakome Joloba
• 金额: $ 7.95万
• 依托单位: MAKERERE UNIVERSITY COLLEGE OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491688
• 关键词: AIDS/HIV problem; Address; Affect; Africa; Animals; Antibiotic Resistance; Antibiotics; Antitubercular Agents; Appearance; Archaea; Arkansas; Bacillus (bacterium); Bacteria; Bacterial Physiology; Basic Science; Biology; Cell Density; Cell Differentiation process; Cell division; Cells; Cellular biology; Chromosomes, Human, Pair 3; Cleaved cell; Clinical; Clinical Microbiology; Condition; Country; Data; Development; Differentiation and Growth; Disease; Doctor of Philosophy; Drosophila genus; Drug Resistant Tuberculosis; Drug resistance; Endopeptidases; Ensure; Epidemic; Epidermal Growth Factor Receptor; Escherichia coli; Eukaryota; Eukaryotic Cell; Exhibits; Facility Construction Funding Category; Faculty; Figs - dietary; Funding; Gene Fusion; Genes; Genetic; Genetic Techniques; Genus Mycobacterium; Gram-Negative Bacteria; Grant; Growth and Development function; HIV; Head; Homologous Gene; Human Resources; Individual; Infection; International AIDS; Knowledge; Laboratories; LacZ Genes; Libraries; Ligands; Medical; Medical Microbiology; Microbial Biofilms; Microbiology; Molecular Biology; Morphology; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Organism; Pathogenesis; Peptide Hydrolases; Peptide Signal Sequences; Peptides; Pharmaceutical Preparations; Phenotype; Physiology; Play; Production; Proteins; Providencia; Receptor Signaling; Regulation; Regulatory Pathway; Reporter; Research; Research Personnel; Research Training; Resistance; Role; Science; Screening procedure; Serine Protease; Signal Transduction; Site; Staging; Students; System; T-Lymphocyte; Testing; Thinking; Training; Tuberculosis; Uganda; United States National Institutes of Health; Universities; Vaccines; Virulence; Wing; Work; Yeasts; compound eye; experience; extracellular; insight; medical schools; member; mycobacterial; novel; novel strategies; programs; quorum sensing; rhomboid; tuberculosis drugs

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), infects 1.7 billion people worldwide. Each year, 2-3 million will eventually die of TB. With the discovery of effective anti-tuberculosis drugs, TB became curable. However, Multi Drug Resistant TB and the recent appearance of extensive drug resistant TB, which in many cases is untreatable, has the potential to make TB an incurable disease once again. The TB epidemic has been worsened by HIV/AIDS. Factors involved in the regulation of many phenotypes of MTB such as virulence, latency, antibiotic resistance and ability to survive under harsh conditions are not well understood. Bacterial cell density dependent signaling (quorum sensing), discovered three decades ago, has been shown to play a major role in the control of virulence, sporulation, antibiotic production, resistance to harsh conditions, cell division, biofilm development and drug resistance in bacteria. Data on the role of quorum sensing on the regulation of MTB phenotypes are limited. The isolation and characterization of genes involved in quorum sensing offer a novel approach in understanding and modifying bacterial physiology. In the proposed study, our broad objective is to identify and characterize genes involved in cell-to-cell signaling in mycobacteria. The specific objectives include: (1) To use genetic techniques to study the role of the Rhomboid-like proteins in the physiology of mycobacteria. This will be achieved by inactivation of rhomboid like genes (quorum sensing genes in other organisms) in M. smegmatis and determining how this affects signal production, morphology, survival and other phenotypes of mycobacteria. (2). To construct a library of quorum sensing regulated gene fusions in mycobacteria. This objective will identify the mycobacterial genes whose regulation is cell density dependent. This will be addressed through construction of random lacZ reporter transcriptional gene fusions in M. smegmatis chromosome. (3) To examine the regulatory pathways of the quorum sensing regulated gene fusions in mycobacteria. This will be achieved through screening for other genes that alter the expression of quorum sensing regulated lacZ gene fusions identified in objective 2. This study will provide further information on quorum sensing regulated mycobacterial functions and also describe the regulatory pathways. This will enrich our knowledge on mycobacterial biology and may reveal novel drug and vaccine targets.

描述(申请人提供)：结核分枝杆菌(MTB)，结核病(TB)的病原体，感染全球17亿人。每年有200-300万人最终死于结核病。随着有效抗结核药物的发现，结核病变得可以治愈。然而，耐多药结核病和最近出现的广泛耐药结核病--在许多情况下是无法治疗的--有可能使结核病再次成为不治之症。结核病流行因艾滋病毒/艾滋病而恶化。结核分枝杆菌许多表型的调控因素，如毒力、潜伏期、抗生素耐药性和在恶劣条件下的生存能力，目前尚不清楚。三十年前发现的细菌细胞密度依赖信号(群体感应)在细菌的毒力、孢子形成、抗生素生产、对恶劣条件的抗性、细胞分裂、生物膜发育和耐药性方面发挥着重要作用。关于群体感应在结核分枝杆菌表型调控中的作用的数据有限。群体感应相关基因的分离和鉴定为理解和修饰细菌生理学提供了新的途径。在这项拟议的研究中，我们的广泛目标是识别和表征分枝杆菌中参与细胞间信号传递的基因。具体目标包括：(1)利用基因技术研究菱形蛋白在分枝杆菌生理学中的作用。这将通过灭活耻垢分枝杆菌中的菱形体样基因(其他生物中的群体感应基因)并确定这如何影响分枝杆菌的信号产生、形态、生存和其他表型来实现。(2)。构建分枝杆菌群体感应调控基因融合文库。这一目标将识别其调控依赖于细胞密度的分枝杆菌基因。这将通过在耻垢分枝杆菌染色体中构建随机LacZ报告转录基因融合来解决。(3)研究分枝杆菌群体感应调控基因融合的调控途径。这将通过筛选目标2中确定的改变群体感应调节的LacZ基因融合表达的其他基因来实现。本研究将提供关于群体感应调节的分枝杆菌功能的进一步信息，并描述调节途径。这将丰富我们对分枝杆菌生物学的知识，并可能揭示新的药物和疫苗靶点。