Carbon monoxide in Mycobacterium tuberculosis pathogenesis

描述（由申请人提供）：项目摘要：Michael夏伊洛博士是一名传染病医生，对宿主-病原体相互作用有明确的兴趣，是纽约市三机构医学科学家培训计划的成员。他的总体职业目标是通过研究M的潜在机制将他的临床和基础科学兴趣联合收割机结合起来。结核病潜伏期在一个学术医疗中心。这个应用程序的构建提供了一个框架来实现这一目标。通过一系列的具体目标，夏伊洛博士将测试几个关于一氧化碳（CO）在M。结核病发病机制具体地说，他将检验由受感染的巨噬细胞产生的CO改变M的代谢和基因表达模式的假设。结核这将使用体外细胞测定以及来自M.肺结核暴露于CO在体外和体内。为了检验M.结核杆菌利用CO在体内生长，M.将测试结核病CO摄取基因在体外、巨噬细胞内和感染小鼠内在CO上生长的能力。最后，为了检验M.结核杆菌抵抗CO的毒性作用，突变体文库将暴露于CO，并且那些在CO存在下不能存活的突变体将被进一步表征。建议的工作是有关确定如何M。结核病能够在肺内建立和维持潜伏感染。此外，该应用程序旨在补充夏伊洛博士先前的实验室经验，并为他提供微生物发病机理方面的必要技术和知识背景，以作为独立的研究者。一个由医生和科学家组成的委员会将监督夏伊洛博士走向独立的进程;他的科学发展也将通过参加加州大学旧金山分校的几个系列研讨会、课程、部门务虚会和全国会议来丰富。UCSF致力于学术医学事业的发展，在资助期结束时，夏伊洛博士将准备开始作为一名独立的医生科学家的职业生涯，调查在受感染宿主中生存的微生物机制。相关性：拟议的工作是相关的，以确定如何M。结核病能够在肺内建立和维持潜伏感染。由于世界上大约三分之一的人口潜伏着M.因此，了解潜伏机制对于开发预防、治疗和根除结核病的新方法至关重要。

DESCRIPTION (provided by applicant): Project Summary: Dr. Michael Shiloh is an infectious disease physician with a well-defined interest in host-pathogen interactions that was fostered as a member of the Tri-lnstitutional medical scientist training program in New York City. His overall career objective is to combine his clinical and basic science interests by studying the underlying mechanisms of M. tuberculosis latency in an academic medical center. This application is constructed to provide a framework to achieve this goal. Through a series of specific aims, Dr. Shiloh will test several hypotheses regarding the role of carbon monoxide (CO) in M. tuberculosis pathogenesis. Specifically, he will test the hypothesis that CO produced by infected macrophages alters the metabolism and gene expression pattern of M. tuberculosis. This will be accomplished using in vitro cellular assays in addition to microarrays from M. tuberculosis exposed to CO in vitro and in vivo. To test the hypothesis that M. tuberculosis utilizes CO for growth in vivo, mutants in the M. tuberculosis CO uptake genes will be tested for their ability to grow on CO in vitro, inside macrophages and inside infected mice. Finally, to test the hypothesis that M. tuberculosis resists the toxic effects of CO, a library of mutants will be exposed to CO and those mutants that fail to survive in the presence of CO will be characterized further. The proposed work is relevant to determining how M. tuberculosis is able to both establish and maintain a dormant infection within the lung. Additionally, this application is designed to complement Dr. Shiloh's prior laboratory experience and provide him with the requisite technical and intellectual background in microbial pathogenesis to function as an independent investigator. A committee of physicians and scientists will oversee Dr. Shiloh's progression towards independence; his scientific development will also be enriched through attendance at several seminar series at UCSF, courses, department retreats and national meetings. UCSF is committed to the development of careers in academic medicine, and at the end of the grant period, Dr. Shiloh will be prepared to embark on a career as an independent physician scientist investigating microbial mechanisms for surviving within the infected host. Relevance: The proposed work is relevant to determining how M. tuberculosis is able to both establish and maintain a latent infection within the lung. Since roughly a third of the world's population harbors a latent infection with M. tuberculosis, understanding the mechanisms involved in latency is vital to developing new ways to prevent, treat and eradicate tuberculosis.