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

描述（由申请人提供）：本提案描述了一个为期五年的结核分枝杆菌研究职业发展计划。结核病）发病机制。该候选人正在接受传染病培训。概述的建议将提供使用正向化学遗传学作为研究微生物致病机制和宿主免疫反应的工具的培训，为在M.结核病发病机制和宿主-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。M.结核病仍然是全球发病率和死亡率的主要原因。对M.结核病毒力的研究将为结核病的治疗提供新的思路。进入人体后，M。结核病很快被巨噬细胞吸收，在那里它成功地逃避被杀死，并建立一种慢性感染形式。它破坏巨噬细胞消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个潜在的强有力的工具，以促进我们的知识操纵巨噬细胞生物学的M。结核本提案概述了研究宿主巨噬细胞与M.结核病使用正向化学遗传学和经典遗传学方法。预计更好地了解M.结核病毒力将为未来治疗药物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抗药性结核病问题。该建议旨在提高我们对感染的理解，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.