Pacific NorthWest Regional Center of Excellence (PNWRCE)

此申请的目标是在NIAID区域X建立太平洋西北地区卓越中心（PNWRCE）。我们选择的两个相互关联但不同的PNWRCE主题不仅反映了我们机构的科学优势，而且反映了我们认为NIAID生物防御和新兴疾病计划中缺乏的未满足的需求。第一个主题“识别免疫系统中与艾滋病相关的缺陷以开发疫苗和补充疗法”将包括两个项目。这些项目的总体目标是为老年人等免疫脆弱人群开发新疫苗和免疫补充疗法。第一个项目P01将研究这样一种假设，即可以进行某些统一的操作，以增加免疫脆弱人群对广泛病原体的T细胞免疫力。第二个项目将开发一种新型有效的疫苗平台，用于安全地对健康和脆弱人群进行YFV免疫接种。第二个主题将集中在“利用系统生物学，功能基因组学和遗传学来表征病原体-宿主反应的生物防御和新出现的疾病生物。“这个主题将包括四个项目，其总体目标是使用系统方法来确定A-C类药物的新靶点和治疗方法。第一个项目P01的目标是使用系统方法来识别增强高致病性肺炎病毒和埃博拉病毒复制和发病机制的常见宿主易感性等位基因和信号通路，并识别影响严重疾病结果的关键细胞靶点和免疫相关性。第二个项目P01的目标是定义先天免疫机制，治疗靶点和限制黄病毒感染和发病机制的抗病毒化合物。第三个项目R 01将使用系统方法来表征弗朗西斯菌突变体，这些突变体表现出细胞内生长速率改变或诱导细胞凋亡。最后一个项目RO 1将使用遗传学、生物化学和计算方法的组合来阐明B。在败血症以及疾病的细胞内阶段期间，假鼻疽宿主病原体应答。

The goal of this application is to establish the Pacific Northwest Regional Center of Excellence (PNWRCE) in NIAID Region X. The two inter-related but distinct PNWRCE themes that we have selected reflect not only the scientific strengths at our institutions but also the unmet needs that we perceive are absent in the NIAID biodefense and emerging disease program. The first theme "Identification of Age-Related Defects in the Immune System to Develop Vaccines and Supplemental Therapies" will include two projects. The overall goal of these projects is to develop new vaccines and immune supplemental therapies for immune vulnerable populations such as aged individuals. The first project a P01 will investigate the hypothesis that certain unifying manipulations can be performed to increase T cell immunity in immune vulnerable populations to a broad group of pathogens. The second project will develop a novel and effective vaccine platform for safely immunizing both healthy and vulnerable populations against YFV. The second theme will center on "The use of systems biology, functional genomics and genetics to characterize pathogen-host response for biodefense and emerging disease organisms." This theme will include four projects with the overall goal of using systems approaches to identify new targets and therapeutics for Category A-C agents. The goal of the first project a P01 is to use systems approaches to identify common host susceptibility alleles and signaling circuitry that enhance highly pathogenic pneumonic viruses and Ebola virus replication and pathogenesis and to identify key cellular targets and immune correlates that influence severe disease outcomes. The goal of the second project a P01 is focused on defining innate immune mechanisms, therapeutic targets, and antiviral compounds that limit flavivirus infection and pathogenesis. The third project an R01 will use systems approaches to characterize Francisella mutants that exhibit either altered intracellular growth rates or induce cellular apoptosis. The last project an RO1 will use a combination of genetic, biochemical, and computational approaches to elucidate B. pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease.