Chemical genetic approach to Vibrio cholerae pathogensis

霍乱弧菌致病的化学遗传学方法

• 批准号: 7062120
• 负责人: DEBORAH T HUNG
• 金额: $ 12.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062120
• 关键词: Vibrio cholerae; bacteria infection mechanism; bacterial genetics; bacterial proteins; bioterrorism /chemical warfare; chemical genetics; cholera; cholera toxin; expression cloning; gene expression; host organism interaction; inhibitor /antagonist; intermolecular interaction; method development; molecular genetics; phenotype; postdoctoral investigator; proteomics; small molecule; transposon /insertion element; virulence

DESCRIPTION (provided by applicant): The goal of this project is to further investigate the regulatory pathways that control virulence expression in Vibrio cholerae, a gram-negative bacterium that causes the human diarrheal disease called cholera. It also is a model organism for understanding bacterial pathogenesis, with the identification of many of its virulence factors and requirements for colonization. Yet, much remains unknown with regards to the organism's mechanisms to sense the environment and respond to virulence activating stimuli. Taking a chemical genetics approach to studying V. choIerae pathogenesis, the candidate has identified 11 novel small molecules that inhibit activation of the virulence genes in V. cholerae. Preliminary studies of these compounds suggest that they define regulatory mechanisms for virulence activation that have not been previously described, including mechanisms to respond to anaerobic conditions and to coordinate virulence expression with biofilm formation. The 11 compounds will be used to identify and characterize these novel pathways. In addition to genetic and biochemical approaches, two new methods will be developed for identifying regulators of virulence expression in V. cholerae. These two methods, a complementation method using a transposon based inducible promoter system and a bacterial-3-hybrid system for identifying small molecule-protein interactions, can be applied to the study of other bacterial systems. The long-term goal of the candidate is to merge the powerful fields of chemical and molecular genetics in the study of bacterial pathogenesis. In this era of increasing microbial resistance to current antibiotics, understanding the basic mechanisms of pathogenesis is critical to finding new solutions. Small molecule effectors and inhibitors may be developed as tools to probe the biology of microbes, providing insight into the organism's requirements for survival in the environment as well as for causing disease in the host. The short-term goal of the candidate is to acquire the skills of molecular bacterial genetics and postgenomic analysis in the laboratory of the sponsor, Dr. John Mekalanos, thus allowing her to become a productive, independent physician-scientist.

描述（由申请人提供）：该项目的目标是进一步研究控制霍乱弧菌毒力表达的调控途径，霍乱弧菌是一种引起人类腹泻疾病霍乱的革兰氏阴性细菌。它也是理解细菌发病机制的模式生物，它的许多毒力因子和定殖需求得到了鉴定。然而，关于生物体感知环境和对毒性激活刺激作出反应的机制，仍有许多未知之处。