Pacific NorthWest Regional Center of Excellence (PNWRCE)

这项申请的目标是在NIAID地区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，也反映了我们认为NIAID生物防御和新兴疾病计划没有满足的需求。第一个主题是“识别免疫系统中与年龄有关的缺陷，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的疫苗和免疫补充疗法。第一个项目P01将调查这样一个假设，即可以执行某些统一的操作来提高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的有效疫苗平台，用于安全地为健康和脆弱人群接种YFV疫苗。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生物防御和新出现的疾病生物体的病原体-宿主反应”。这一主题将包括四个项目，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常见的宿主易感性等位基因和信号回路，以增强高致病性肺炎病毒和埃博拉病毒的复制和致病机制，并确定影响严重疾病结局的关键细胞靶点和免疫相关因素。第二个项目A P01的目标是确定限制黄病毒感染和发病的先天免疫机制、治疗靶点和抗病毒化合物。第三个项目AN R01将使用系统方法来表征弗朗西斯菌突变株，这些突变株要么表现出细胞内生长速度的变化，要么诱导细胞凋亡。最后一个项目ANRO1将使用遗传、生化和计算方法的组合来阐明假鼻疽杆菌在败血症以及疾病的细胞内阶段的宿主病原体反应。

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.