Agents of Bioterrorism: Pathogenesis and host defense

说明(申请人提供)：人们非常关注在蓄意的生物恐怖主义行为中重新使用生物制剂的可能性，以及如果再次尝试成为现实，保护公众健康的必要性。为了迎接这一挑战，生物恐怖主义A类毒剂的发病机制和宿主防御的基础研究已经成为可能。在本计划项目拨款申请中，作为对生物防御和新发传染病研究倡议的响应，一组对图拉氏方济氏菌、汉坦病毒和鼠疫耶尔森菌有经验的科学家将合作进行一个综合项目，该项目将研究：1)鼠疫杆菌在巨噬细胞中的生存和复制机制；项目1，James Bliska。2)图拉氏丝虫与炎症细胞和先天免疫系统细胞相互作用的新机制；项目2，Martha Furie。3)鼠疫杆菌和图拉氏杆菌原核生物SmpB-SsrA质量控制系统的生化作用，特别强调抗菌治疗及其在抗感染药物发现中的应用；项目3，瓦利·卡尔扎伊。4)调节细胞干扰素反应和确定致病汉坦病毒信号通路调节机制的汉坦病毒蛋白；项目4，Erich Mackow。5)鼠疫杆菌和图拉氏杆菌的毒力因子，并阐明这些病原体的毒力因子组装和分泌机制；项目5，David Thanassi。这个 研究项目将得到三个核心的支持。核心A将处理所有行政、开发和实验室安全事务，并将由PI Jorge Benach领导。核心B是微阵列，由Bruce Futcher领导的生物信息学核心将为鼠疫杆菌和图拉氏杆菌的基因组生产斑点DNA微阵列，并制作定制的人类微阵列。CORE B将为所有微阵列实验提供建议和协助，并为最先进的生物信息学提供所有数据解释。Core C将为所有项目生产克隆抗体。包括在BSL3Ag环境中对小鼠的气溶胶感染在内的多学科方法有望成为满足这些试剂的基础研究需求以及开发该计划项目的诊断和治疗方面的强大工具。

DESCRIPTION (provided by applicant): There is much concern about the possibility of renewed use of biological agents in intentional acts of bioterrorism, and the necessity to protect the public's health if renewed attempts were to become a reality. To meet this challenge, new avenues for basic research on the pathogenesis of and host defense to Category A agents of Bioterrorism have become available. In this Program Project Grant application in response to initiatives on Biodefense and Emerging Infectious Disease Research, a group of scientists with previous experience with Francisella tularensis, hantaviruses, and Yersinia pestis will collaborate in a comprehensive project that will study: 1) the mechanisms of survival and replication of Y. pestis in macrophages; Project 1, James Bliska. 2) the novel mechanisms of F. tularensis interaction with cells of the inflammatory and innate immune systems; Project 2, Martha Furie. 3) the biochemical role of the prokaryotic SmpB-SsrA quality control system of Y. pestis and F. tularensis with particular emphasis on antibacterial therapy and its utility in anti-infective drug discovery; Project 3, Wali Karzai. 4) the hantavirus proteins that regulate cellular IFN responses and define mechanisms of signaling pathway regulation by pathogenic hantaviruses; Project 4, Erich Mackow. 5) the virulence factors of Y. pestis and F. tularensis and to elucidate the mechanisms of virulence factor assembly and secretion by these pathogens; Project 5, David Thanassi. The Research Projects will be supported by three Cores. Core A will deal with all administrative, development, and laboratory security matters and it will be headed by the PI, Jorge Benach. Core B is the Microarray and Bioinformatics Core headed by Bruce Futcher will produce spotted DNA microarrays for the genomes of F. pestis and F. tularensis, and make custom human microarrays. Core B will provide advice and assistance with all microarray experiments; and with all data interpretation with state of the art Bioinformatics. Core C will produce monoclonal antibodies for all of the Projects. A multidisciplinary approach including aerosol infections of mice in a BSL3Ag setting is expected to be a powerful tool for the basic research needs of these agents, and for the development of the diagnostic and therapeutic aspects of this Program Project.