Chemical genetic approach to cellular mechanisms of M. tuberculosis virulence.

结核分枝杆菌毒力细胞机制的化学遗传学方法。

• 批准号: 8150390
• 负责人: Amy K Barczak
• 金额: $ 13.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150390
• 关键词: Address; Bacillus (bacterium); Bacteria; Biological Assay; Biology; Cells; Chemicals; Chronic; Communicable Diseases; Critical Pathways; Development; Disease; Drug Resistant Tuberculosis; Face; Future; Genetic; Genus Mycobacterium; Health; Host Defense; Human; Image; Immune response; Immune system; Infection; Infection Control; Infectious Disease Immunology; Integration Host Factors; Knowledge; Libraries; Mediating; Mentorship; Microbiology; Molecular; Molecular Genetics; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mycobacterium Infections; Mycobacterium tuberculosis; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physicians; Play; Preparation; Public Health Schools; Research; Role; Scientist; Serotonin Antagonists; Serotonin Receptor 5-HT2A; Therapeutic; Training; Tuberculosis; Virulence; Work; career; career development; chemical genetics; high throughput screening; inhibitor/antagonist; insight; interest; killings; latent infection; macrophage; medical schools; microbial; mortality; mutant; mycobacterial; novel strategies; novel therapeutics; pathogen; prevent; professor; programs; reactivation from latency; small molecule; therapeutic target; therapy development; tool; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): This proposal describes a five year research career development program in the study of Mycobacterium tuberculosis (M. tuberculosis) pathogenesis. The candidate is training in Infectious Diseases. The outlined proposal will provide training in the use of forward chemical genetics as a tool for studying mechanisms of microbial pathogensis and the host immune response, in preparation for a career as an independent physician-scientist in the field of M. tuberculosis pathogenesis and the host-pathogen interface. The work will be conducted under the mentorship of Dr. Deborah Hung, Assistant Professor of Microbiology and Molecular Genetics and Harvard Medical School, and Dr. Eric Rubin, Associate Professor of Immunology and Infectious Disease at Harvard School of Public Health. M. tuberculosis remains a major cause of morbidity and mortality globally. A detailed understanding of molecular mechanisms of M. tuberculosis virulence would offer insight into new approaches to the treatment of tuberculosis. Upon entering the human host, M. tuberculosis is quickly taken up into macrophages, where it successfully evades being killed and establishes a chronic form of infection. The mechanisms by which it subverts macrophage pathways for eliminating intracellular bacteria are not well-described. Forward chemical genetics is a potentially powerful tool to advance our knowledge of manipulation of macrophage biology by M. tuberculosis. This proposal outlines a plan to to investigate the details of interactions between host macrophages and M. tuberculosis using both a forward chemical genetic and a classical genetic approach. It is anticipated that a better understanding of molecular details of M. tuberculosis virulence will offer new potential targets for the development of future therapeutics. Tuberculosis remains an important threat to health globally. Our current medications are inadequate to face the growing problems of tuberculosis and drug-resistant tuberculosis. This proposal aims to enhance our understanding of infection, to offer new possibilities for future treatment development.

描述（由申请人提供）：该提案描述了一项为期五年的研究职业发展计划，以研究结核分枝杆菌（结核分枝杆菌）发病机理。候选人是接受传染病的培训。概述的提案将提供培训，以使用前远上的化学遗传学作为研究微生物病原体和宿主免疫反应机制的工具，以准备在结核分枝杆菌发病机理和宿主病原体界面领域成为独立的医生 - 科学家的职业。这项工作将在微生物学和分子遗传学助理教授和哈佛医学院的助理教授Deborah Hung博士以及哈佛公共卫生学院免疫学和传染病副教授Eric Rubin博士的指导下进行。肺结核M.在全球范围内仍然是发病率和死亡率的主要原因。对结核分枝杆菌毒力的分子机制的详细理解将洞悉治疗结核病的新方法。进入人类宿主后，结核分枝杆菌很快就会陷入巨噬细胞，在那里成功逃避被杀死并建立了一种慢性的感染形式。它颠覆消除细胞内细菌的巨噬细胞途径的机制尚未很好地描述。远期化学遗传学是一种潜在的强大工具，可以通过结核分枝杆菌促进我们对巨噬细胞生物学操纵的了解。该提议概述了一个计划，以研究寄托巨噬细胞和结核分枝杆菌之间相互作用的细节，同时既有化学遗传和经典遗传学方法。可以预料，对结核分枝杆菌毒力的分子细节有更好的了解将为未来治疗剂的发展提供新的潜在靶标。 结核病仍然是对全球卫生的重要威胁。我们目前的药物不足以面对结核病和耐药性结核病的日益增长的问题。该建议旨在增强我们对感染的理解，为未来的治疗开发提供新的可能性。