Carbon monoxide in Mycobacterium tuberculosis pathogenesis

项目简介：Michael Shiloh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在学术医疗中心研究结核分枝杆菌潜伏期的潜在机制，将他的临床和基础科学兴趣结合起来。构建此应用程序是为了提供实现此目标的框架。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）在结核分枝杆菌发病机制中的作用的假设。具体来说，他将验证感染巨噬细胞产生的CO改变结核分枝杆菌代谢和基因表达模式的假设。这将通过体外细胞测定以及暴露于CO的结核分枝杆菌微阵列来完成。为了验证结核分枝杆菌利用CO在体内生长的假设，将在体外、巨噬细胞内和感染小鼠体内测试结核分枝杆菌CO摄取基因突变体在CO上生长的能力。最后，为了验证结核分枝杆菌抵抗CO毒性作用的假设，将一个突变体库暴露于CO中，并进一步表征那些在CO存在下无法存活的突变体。拟议的工作与确定结核分枝杆菌如何能够在肺内建立和维持休眠感染有关。此外，该申请旨在补充Shiloh博士之前的实验室经验，并为他提供微生物发病机理作为独立研究者所需的技术和知识背景。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；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、部门务虚会和国家会议而得到丰富。UCSF致力于学术医学事业的发展，在资助期结束时，Shiloh博士将准备开始作为一名独立的内科科学家的职业生涯，研究受感染宿主体内的微生物生存机制。相关性：提出的工作与确定结核分枝杆菌如何能够在肺内建立和维持潜伏感染有关。由于世界上大约三分之一的人口患有结核分枝杆菌潜伏感染，因此了解潜伏感染的机制对于开发预防、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.