SYSTEMS BIOLOGY OF HOST-PATHOGEN INTERACTIONS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 Ross P. Carlson是“宿主-病原体相互作用的系统生物学”项目的PL。卡尔森正在构建病原体代谢模型，进行基本通量模式分析，以及设计，运行和分析恒化器实验。卡尔森博士将监督博士后研究助理和研究生。 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品的蛋白质组学分析。博士后也将帮助研究生的监督。 研究生将在该项目的第二年开始。研究生将运行分析，并优化恒化培养，使培养基和其他试剂，订购用品，照顾文化和维护设备。 病原体对宿主免疫系统反应的代谢基础知之甚少。据推测，宿主-病原体相互作用的系统分析将揭示，解释和量化代谢适应的致病性至关重要。基于系统的理解宿主-病原体相互作用的承诺，以促进新的治疗策略的发展，提高特异性和减少副作用的疾病治疗。宿主-病原体研究将把酶水平和活性的蛋白质组学分析以及定量代谢通量分析与数学定义的计算机化框架相结合，以研究病原体毒力机制和宿主防御机制。 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和白色念珠菌以及宿主巨噬细胞的计算机代谢模型来识别系统的关键组件，2）在病原体适应与感染相关的压力之后，通过计算机模拟和体外实验来研究组件如何工作，和3）通过测量和模拟感染期间宿主和病原体的同时代谢适应来确定组分如何一起工作以实现生物学机制。然而，先前报道的吞噬体中吞噬的病原体的转录组研究为拟议的工作提供了实验基础; mRNA和蛋白质水平之间的相关性通常很低，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所改变，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.