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

描述(由申请人提供)：本建议书描述了一个研究结核分枝杆菌(结核分枝杆菌)发病机制的五年研究生涯发展计划。这位候选人正在接受传染病方面的培训。概述的提案将提供使用正向化学遗传学作为研究微生物致病机制和宿主免疫反应机制的工具的培训，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内科科学家做准备。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。对结核分枝杆菌毒力的分子机制的详细了解将为结核病的治疗提供新的方法。一旦进入人类宿主，结核分枝杆菌就会迅速进入巨噬细胞，在那里它成功地逃脱了被杀死的命运，并建立了一种慢性感染形式。它颠覆巨噬细胞清除细胞内细菌的途径的机制还没有得到很好的描述。正向化学遗传学是一种潜在的强大工具，可以促进我们对结核分枝杆菌操纵巨噬细胞生物学的了解。这项建议概述了一项计划，以研究宿主巨噬细胞和结核分枝杆菌之间相互作用的细节，同时使用正向化学遗传方法和经典遗传方法。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的发展提供新的潜在靶点。 结核病仍然是全球健康的重要威胁。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。这项建议旨在提高我们对感染的认识，为未来的治疗发展提供新的可能性。

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.