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: 8318274
• 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/8318274
• 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）：该提案描述了结核分枝杆菌（M. tuberculosis）发病机制研究的五年研究职业发展计划。该候选人正在接受传染病培训。概述的提案将提供使用正向化学遗传学作为研究微生物发病机制和宿主免疫反应机制的工具的培训，为结核分枝杆菌发病机制和宿主领域的独立医师科学家职业生涯做好准备-病原体界面。这项工作将在哈佛医学院微生物学和分子遗传学助理教授 Deborah Hung 博士和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。结核分枝杆菌仍然是全球发病和死亡的主要原因。详细了解结核分枝杆菌毒力的分子机制将为治疗结核病的新方法提供见解。进入人类宿主后，结核分枝杆菌很快被巨噬细胞吸收，并成功逃脱被杀死并形成慢性感染。它破坏巨噬细胞途径以消除细胞内细菌的机制尚未得到很好的描述。正向化学遗传学是一种潜在的强大工具，可以增进我们对结核分枝杆菌操纵巨噬细胞生物学的了解。该提案概述了一项计划，利用正向化学遗传学和经典遗传学方法来研究宿主巨噬细胞和结核分枝杆菌之间相互作用的细节。预计更好地了解结核分枝杆菌毒力的分子细节将为未来治疗方法的开发提供新的潜在靶点。 结核病仍然是全球健康的一个重要威胁。我们目前的药物不足以应对日益严重的结核病和耐药结核病问题。该提案旨在增强我们对感染的认识，为未来治疗的发展提供新的可能性。