SYSTEMS BIOLOGY OF HOST-PATHOGEN INTERACTIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 罗斯·P·卡尔森是“寄主-病原体相互作用的系统生物学”项目的首席研究员。卡尔森博士正在构建病原体代谢模型，执行基本的通量模式分析，以及设计、运行和分析恒化器实验。卡尔森博士将监督一名博士后助理研究员和这名研究生。博士后研究助理将建立和完善代谢模型，使用DATA MIR进行基本模式分析，分析恒化器实验，以及执行和分析实验样本的蛋白质组分析。博士后还将帮助指导研究生。 研究生将在该项目的第二年开始。这位研究生将负责分析和优化恒化器培养，制作介质和其他试剂，订购用品，护理培养物和维护设备。 病原体对宿主免疫系统反应的代谢基础还知之甚少。据推测，对宿主-病原体相互作用的系统分析将揭示、解释和量化对致病性至关重要的代谢适应。以系统为基础了解宿主-病原体的相互作用有望促进开发新的疾病治疗策略，提高特异性并减少副作用。寄主-病原菌研究将结合酶水平和活性的蛋白质组学分析和定量代谢通量分析，以及研究病原菌毒力机制和寄主防御机制的数学定义的计算机化框架。 这是一个自下而上的系统生物学项目，旨在：1)通过构建和分析病原体大肠杆菌、白色念珠菌和宿主巨噬细胞的电子代谢模型来识别系统的关键组件，2)通过计算机模拟和体外实验研究这些组件是如何工作的，跟随病原体适应与感染相关的压力，以及3)通过测量和模拟宿主和病原体在感染过程中的同时代谢适应来确定这些组件如何协同工作来完成生物机制。以前报道的对吞噬小体中病原体的转录组研究为拟议的工作提供了实验基础；然而，mRNA和蛋白质水平之间的相关性往往很低，在某些情况下，甚至是负的。此外，蛋白质的活性经常被翻译后修饰改变，这必须直接在蛋白质水平上进行研究。了解宿主-病原体相互作用的基本系统生物学将为最终开发合理的传染病“系统疗法”提供所需的知识。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ross P. Carlson is the PL on the 'Systems Biology of Host-Pathogen Interaction' project. Dr. Carlson is constructing pathogen metabolic models, perform elementary flux mode analysis, as well as design, run, and analyze chemostat experiments. Dr. Carlson will oversee a post-doctoral research associate and the graduate student. The Post-doctoral research associate will build and refine metabolic models, perform elementary modes analysis with data mir and analyze chemostat experiments as well as perform and analyze proteomic analysis of experimental samples. The post-doc will also aid in the supervision of the graduate student. The Graduate student will start in the second year of the project. The graduate student will run analyze, and optimize chemostat cultures, make medium and other reagents, order supplies, care for cultures and maintain equipment. The metabolic basis of pathogen responses to the host immune system is poorly understood. It is hypothesized that a systems analysis of host-pathogen interactions will reveal, explain, and quantify metabolic adaptations critical for pathogenicity. A systems-based understanding of host-pathogen interactions promises to facilitate the development of novel therapeutic strategies for disease treatment with increased specificity and reduced side-effects. The host-pathogen research will integrate proteomic analysis of enzyme levels and activities and quantitative metabolic flux analysis with a mathematically defined, computerized framework to study pathogen virulence mechanisms and host defense mechanisms. This is a "bottom-up" systems biology project that aims to: 1) identify the critical components of the systems by constructing and analyzing in silico metabolic models of the pathogens Escherichia coli and Candida albicans and the host macrophage cells, 2) study how the components work through computer simulations and in vitro experiments following pathogens adapting to stresses associated with infection, and 3) determine how the components can work together to accomplish the biological mechanism by measuring and modeling the simultaneous metabolic adaptations of both host and pathogen during infection. Previously reported transcriptome studies of pathogens engulfed in phagosomes provide an experimental footing for the proposed work, however; the correlation between mRNA and protein levels is often low and in some cases, even negative. In addition, protein activities are often altered by post-translational modifications which must be studied directly at the protein level. Understanding the basic systems biology of host-pathogen interactions will provide knowledge needed to ultimately develop rational 'systems therapy' for infectious diseases.