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）：本提案描述了一个为期五年的研究生涯发展计划，研究结核分枝杆菌（M. tuberculosis）的发病机制。这位候选人正在接受传染病方面的培训。概述的建议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的工具的培训，为成为结核分枝杆菌发病机制和宿主-病原体界面领域的独立医生-科学家做准备。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率和死亡率的主要原因。详细了解结核分枝杆菌毒力的分子机制将为结核病治疗的新方法提供见解。在进入人类宿主后，结核分枝杆菌很快被巨噬细胞吸收，在那里它成功地逃避了被杀死，并建立了一种慢性感染形式。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，可以提高我们对结核分枝杆菌操纵巨噬细胞生物学的认识。本提案概述了一项计划，以研究宿主巨噬细胞和结核分枝杆菌之间的相互作用的细节，同时使用正向化学遗传学和经典遗传学方法。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发展提供新的潜在靶点。