Administration Core

行政核心

• 批准号: 7675839
• 负责人: Samuel I Miller
• 金额: $ 120.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675839
• 关键词: AIDS Vaccines; Acids; Acquired Immunodeficiency Syndrome; Adjuvant; Airway Resistance; Alaska; Alkaline Phosphatase; Animal Feed; Animal Model; Antibiotic Resistance; Antibiotics; Area; Asia; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Basic Science; Biochemistry; Biodiversity; Biohazardous Substance; Biological; Biological Assay; Biological Models; Biology; Biomedical Research; Biotechnology; Bioterrorism; Books; Breathing; British Columbia; Brucella abortus; Burkholderia; Burkholderia mallei; Burkholderia pseudomallei; Canada; Categories; Cause of Death; Cell Death; Centers of Research Excellence; Clinical; Collaborations; Communicable Diseases; Communities; Complement; Cystic Fibrosis; Cytolysis; DNA Sequence; Development; Disease; Disease Outbreaks; Elements; Emergency Situation; Emerging Communicable Diseases; Engineering; Enteral; Environment; Enzymes; Event; Evolution; Ferrets; Flagellin; Food; Francisella; Francisella tularensis; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetically Modified Organisms; Genome; Genomics; Geographic Locations; Geography; Glanders; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Grant; Health; Health Personnel; Health Sciences; Human; Human Characteristics; Idaho; Immune; Immune response; Immune system; Immunologic Adjuvants; Immunologic Receptors; Immunologic Surveillance; Immunology; Immunomodulators; In Vitro; Inbred Mouse; Individual; Infection; Infection Control; Infectious Agent; Infectious Diseases Research; Inflammation; Inflammatory; Ingestion; Insect Vectors; Institutes; Institution; International; Intestines; K-Series Research Career Programs; Knowledge; Laboratories; Leadership; Ligands; Lipid A; Lung diseases; Mammalian Cell; Mammals; Maryland; Medical center; Medicine; Melioidosis; Membrane; Mexico; Microbiology; Modeling; Molecular; Montana; Mus; NCI Center for Cancer Research; National Institute of Allergy and Infectious Disease; National Security; Nature; Oral; Oregon; Organism; Oxidative Stress; Pacific Northwest; Pathogenesis; Pathology; Pathway interactions; Pediatric Hospitals; Pediatrics; Performance; Phagocytes; Phagocytosis; Phagolysosome; Pharmacologic Substance; Phenotype; Physiological; Plague; Plants; Play; Population; Positioning Attribute; Preclinical Testing; Predisposition; Process; Property; Proteins; Proteomics; Protozoa; Pseudomonas aeruginosa; Public Health; Recruitment Activity; Research; Research Institute; Research Personnel; Research Project Grants; Resources; Rodent; Role; Route; Salmonella typhimurium; Science; Sexually Transmitted Diseases; Signal Transduction; Site; Source; Southeastern Asia; Staging; Stress; Structure; Surface; Sweden; System; Systems Biology; TLR4 gene; Technology; Thailand; Therapeutic; Toxin; Training; Training Programs; Training and Education; Translating; Translations; Transportation; Tularemia; Type II Secretion System Pathway; Type III Secretion System Pathway; USSR; United States; United States National Institutes of Health; Universities; Vaccines; Vacuole; Variant; Virulence; Virulence Factors; Virulent; Washington; Work; Yersinia; Yersinia pestis; antimicrobial peptide; bacterial resistance; base; biodefense; bis(3' ,5' )-cyclic diguanylic acid; cell type; combat; drug development; genome sequencing; improved; in vitro Assay; killings; knowledge base; lymph nodes; macrophage; medical schools; meetings; member; monocyte; next generation; nitrosative stress; novel; pathogen; periplasm; prevent; programs; quorum sensing; research and development; resistance mechanism; resistant strain; response; structural biology; structural genomics; success; therapeutic development; therapeutic vaccine; transmission process; vaccine candidate; vaccine development; vaccine evaluation; weapons

The Region X Northwest Regional Center of Excellence (NWRCE) for Biodefense and Emerging Infectious Diseases is an essential component in a nationwide network of biomedical research programs to combat infectious disease threats to the population. The NWRCE is currently a highly interactive and thematic program focused on Gram-negative bacterial pathogens. The same general consistent focus has existed since its inception. There are three themes: (1) mechanisms of Gram-negative bacterial pathogenesis, (2) innate immune responses to Gram-negative bacterial pathogens, and (3) translation of (1) and (2) into early stage therapeutic development to prevent or treat Gram-negative bacterial diseases. The NWRCE is centered at the University of Washington (UW) in Seattle; in this renewal application, multiple sites are proposed in Seattle, two in Oregon, one in Idaho, and one in Maryland. The NWRCE has included the NIAID Rocky Mountain Laboratory since its inception and this relationship will continue and grow as part of this renewal as collaborations are expanded to include tularemia as well as plague research. British Columbia is also in our geographic region and collaboration is proposed with the University of Victoria, British Columbia. The NWRCE renewal proposes three international sites: Thailand, Sweden, and Mexico. The projects, cores, domestic and international sites, as well as collaborators, are highly interactive. The individuals that make up this proposal have worked together for many years during the last funding period and before the RCE was funded. The majority of investigators newly added to this to this application for renewed funding of the NWRCE have had long collaborative relationships with members of the center. The interactive nature and focus of the NWRCE is a major strength of the program and allows the NWRCE to rapidly and nimbly respond to national priorities to achieve important objectives with respect to Gram-negative bacterial infections. The Seattle biomedical community occupies a unique international leadership position in infectious diseases research and global health and hence centering such a program at the UW is logical for both national and regional needs. The UW Medical School has traditionally emphasized its infectious disease research program. The training programs in infectious diseases, microbiology, immunology, global health, and genome sciences are highly successful, interactive, and comprehensive. The UW currently has five NIH funded training grants in infectious diseases research that have trained hundreds of individuals over the last 30 years, many of them now leaders in the field. Infectious diseases research at the UW permeates many of the clinical and basic science departments, including Global Health, Medicine, Pediatrics, Genome Sciences, Microbiology, Immunology, Biochemistry, and Structural Biology. Currently, more than four hundred trainees are engaged in infectious disease research in these departments. Furthermore, these departments host a variety of centers and cooperative research programs studying infectious diseases, such the Center for AIDS Research and the Sexually Transmitted Diseases Cooperative Research Center, and the Department of Global Health, all directed by Dr. King Holmes. Other centers include the AIDS Vaccine Evaluation Unit directed by Dr. Julie McElrath, the Cooperative Research Center for Structural Genomics of Pathogenic Protozoa directed by Dr. Wim Hoi, and the Cystic Fibrosis Research and Development Program directed by Dr. Peter Greenberg. These centers involve cooperative research consortia that have been assembled from a variety of departments to study specific infectious disease problems. The cooperative research culture and environment at the UW greatly facilitated development of the NWRCE, since a cooperative spirit and culture was required to establish the NWRCE as a thematic interactive center. Such a cooperative environment will be essential for continued success in achieving the programmatic goals of the NIAID and the national infectious diseases agenda. There are many institutions in the region with established connections to the UW that also have strong microbiology and infectious diseases research programs, including many that participate and collaborate with the NWRCE. These institutions include the Fred Hutchinspn Cancer Research Center, the Children's Hospital and Regional Medical Center, the Institute for Systems Biology, PATH, the Infectious Disease Research Institute, and the Seattle Biomedical Research Institute (containing the NIAID funded structural biology center which collaborates with the NWRCE) among others. Other important institutions with infectious disease research programs in the region include the Rocky Mountain Laboratories of the NIAID, Pacific Northwest National Laboratories (Containing an NIAID funded Proteomics Center), the Universities of Alaska, Idaho, and Oregon, the Oregon Health Sciences Center, Oregon State University, Montana State University, and Washington State University. The majority of these institutions have been funded in the last five years through the NWRCE. Investigators at Montana State were initially funded through the NWRCE and then became an established component of the Rocky Mountain RCE (Dr. David Pascual). Investigators at the Guillemen). The Pacific Northwest (and specifically Seattle) is also one of the centers in the United States for biotechnology companies, many of which focus on infectious diseases and inflammation research, including Amgen (formerly Immunex). The geography of the NWRCE region is also uniquely important for biodefense and emerging infectious diseases in that it is situated on the northwestern coast of the United States, bordering Canada and serving as a transportation portal to Asia. This unique group of NWRCE-associated institutions forms a powerful base of resources for the NWRCE. In addition, the NWRCE has established important international collaborations to facilitate its disease-based activities in characterization of pathogen diversity with the establishment of centers in Thailand, Sweden, and Mexico to collaborate with NWRCE investigators on projects in melioidosis, tularemia, and enteric and other emerging Gram-negative bacterial infectious diseases. As a central hub in this network of affiliations, and as a leader in infectious diseases research, the NWRCE is prepared to continue to advance its role as a world leader in Gram-negative bacterial pathogenesis, immune responses, and therapeutic development and to train the next generation of researchers in this important area. There is a strong rationale for a continued program primarily focused on Gram-negative agents. There are several reasons why Gram-negative bacteria should be an important focus of study. Gram-negative bacteria have a common surface structure with two membranes separated by a periplasmic space. Two of the NIAID-classified Category A agents on the biodefense agenda are Gram-negative bacteria, as are the majority of Category B agents. Human infection with Gram-negative bacteria can be readily acquired through inhalation and oral ingestion, both routes that can be easily utilized in a biological attack. Gram-negative bacterial antibiotic resistance is increasing and, in contrast to Gram-positive bacteria, pharmaceutical companies have little in the drug development pipeline for these organisms. Many Gram-negative bacteria are also pathogens of food animals and could be used to attack food sources. Additionally, as important plant pathogens, Gramnegative bacteria also represent a significant threat to food crops, either as naturally emerging pathogens or as agents of biological terrorism. A variety of enteric and respiratory diseases have been utilized for many years as biological weapons because of their stability, potential for weaponization, and the ease with which they can be genetically engineered. In the book Biohazard, author Ken Alibek describes the former Soviet Union's biological weapons program, which focused on the Gram-negative organisms F. tularensis, Y. pestis, B. pseudomallei, B. mallei and Brucella abortus [1]. Alibek describes the development of two classes of genetically modified organisms: new antibiotic-resistant strains, and strains rendered more virulent by inclusion of toxin genes from another species. One example of the latter involved the addition of 8. pseudomallei toxin genes to F. tularensis. With the development of "super-bioweapons" using Gram-negative bacteria already an actuality, the need to expand our base of knowledge about the unique virulence factors and pathology of Gram-negative bacteria is particularly urgent. Consistent with this information, the Gram-negative bacteria Y. pestis (YP) and F. tularensis (FT) are main research foci of this proposal. Furthermore, because of its importance as an understudied pathogen that is endemic in Southeast Asia (to which the Northwest region serves as a transportation portal) and its possible use in biological attack, the Category B agent B. pseudomallei (BP) (and the closely related glanders agent B mallei, BM) will also be a research focus of the NWRCE. Research on Gram-negative bacteria such as ¿ cpli, Salmpnellae and Yersinia spp. has identified important conserved structural elements and mechanisms of virulence. The envelope of Gram-negative bacteria contains conserved molecules such as LPS, flagellin, and lipopeptides, which stimulate innate immune responses. The bacteria also contain conserved mechanisms to manipulate or modulate these responses by regulating the structure and synthesis of molecules such as LPS and flagellin and delivering enzymes which alter host responses. These organisms also have conserved mechanisms of resistance to killing by host innate immune effector molecules such as antimicrobial peptides and oxidative stress. Gramnegative bacteria have conserved mechanisms of secretion of virulence proteins that have conserved enzymatic activity to manipulate host processes and cause death. However, each pathogen has its unique complement of these properties and there is tremendous biological diversity among both the bacteria, which are constantly evolving, and humans, whose evolution was driven in part by bacterial pathogens and commensals. Therefore much more knowledge must be generated, particularly knowledge of current pathogens so that this knowledge can be effectively translated. This proposal is therefore focused on understanding the basic and unique biology of Gram-negative bacteria with a focus on these understudied organisms of national importance. Although YP, FT, and BP have some common features in being Gram-negative pathogens that infect the airway, they also have important differences. While all survive mammalian innate immune attack to promote disease, YP and FT have relatively non-inflammatory LPS structures [2, 3] while that of BP is inflammatory. YP inhibits phagocytosis [4] while FT and BP escape from the phagolysosome by lysis of the vacuole, where they activate cytosolic innate immune surveillance pathways [5]. Both YP and BP use multiple type III secretion systems as pathogenic strategies [6, 7], while FT uses a type II secretion system [8]. FT has a small genome [8] while BP has a large genome that is more closely related to Pseudomonas aeruginosa and Burkholderia 9-11]. FT and YP are transmitted by insect vectors [9, 11], and reside in small mammal reservoirs throughout the U.S. and the world. Interestingly, the attempt to reintroduce black ferrets into the wild regions of Montana in the summer of 2007 was limited by Y. pestis transmission from wild rodents which serve as a major ferret food source. BP has both plant and environmental reservoirs throughout Southeast Asia [10]. The nature and diversity of the organisms in these reservoirs must be understood for national security. It is also important to understand the nature of human diversity in response to these organisms so that in the case of national emergency priorities can be set and strategies can be developed that will utilize compounds which target our own immune systems to combat infectious diseases. While vaccines exist for FT and YP, these vaccines provide no protection against inhalation disease [12, 13]. The NWRCE developed early stage vaccine candidates in the last project period to combat these diseases. No vaccine exists for BP [14]. The NWRCE developed therapeutic candidates in the last project period that may have broad spectrum efficacy against these pathogens by augmenting innate immune responses and blocking bacterial secretion. The NWRCE will increase knowledge of the basic biology of these important infectious agents and translate this information into vaccines and compounds that will be broad spectrum therapeutics useful in the event of a biological attack and/or a naturally occurring outbreak. The unique qualifications of the NWRCE investigators in Gram-negative bacterial research and innate immune response provide an additional rationale for this proposal's focus.

X 区西北生物防御和新兴区域卓越中心 (NWRCE) 传染病是全国生物医学研究网络的重要组成部分 NWRCE 目前是一个高度重视对抗传染病威胁的计划。 互动和主题节目重点关注革兰氏阴性细菌病原体。 自成立以来一直存在着三个主题：（1）革兰氏阴性菌的机制。 细菌发病机制，(2) 对革兰氏阴性细菌病原体的先天免疫反应，以及 (3) 将（1）和（2）转化为预防或治疗革兰氏阴性菌的早期治疗开发 NWRCE 的这次更新以西雅图华盛顿大学 (UW) 为中心； 根据申请，提议在西雅图设立多个站点，在俄勒冈州设立两个站点，在爱达荷州设立一个站点，在马里兰州设立一个站点。 NWRCE 自 NIAID 落基山实验室成立以来就已将其纳入其中，这种关系将 作为这一更新的一部分，随着合作范围扩大到包括兔热病以及 不列颠哥伦比亚省也在我们的地理区域内，并提议与该地区进行合作。 不列颠哥伦比亚省维多利亚大学 NWRCE 更新提议三个国际校区：泰国、 瑞典和墨西哥的项目、核心、国内和国际站点以及合作者都高度评价。 制定本提案的个人在过去已经合作多年。 资助期间和 RCE 资助之前，大多数研究者都是新添加到此的。 NWRCE 的续资申请与 NWRCE 的成员有着长期的合作关系 NWRCE 的互动性和重点是该计划的主要优势，并允许 NWRCE 快速灵活地响应国家优先事项，以实现以下方面的重要目标： 革兰氏阴性细菌感染。 西雅图生物医学界在传染病领域占据着独特的国际领导地位 疾病研究和全球健康，因此将这样一个项目集中在华盛顿大学对两者来说都是合乎逻辑的 华盛顿大学医学院传统上强调其传染病。 研究计划。传染病、微生物学、免疫学、全球健康和 基因组科学非常成功、互动且全面。华盛顿大学目前拥有五个 NIH。 资助了传染病研究方面的培训补助金，在过去 30 年中培训了数百人 多年来，他们中的许多人现在是华盛顿大学传染病研究领域的领导者。 临床和基础科学部门，包括全球健康、医学、儿科、基因组科学、 微生物学、免疫学、生物化学和结构生物学目前有四百多名学员。 在这些科室从事传染病研究。 研究传染病的各种中心和合作研究项目，例如艾滋病中心 研究与性传播疾病合作研究中心和全球部 健康中心均由 King Holmes 博士领导。其他中心包括由 King Holmes 博士领导的艾滋病疫苗评估中心。 Julie McElrath 博士，致病性原生动物结构基因组学合作研究中心 由 Wim Hoi 博士负责，囊性纤维化研究与开发计划由 Peter Greenberg 博士负责。 这些中心涉及由不同部门组成的合作研究联盟 研究特定的传染病问题 华盛顿大学的合作研究文化和环境。 极大地促进了 NWR​​CE 的发展，因为需要合作精神和文化来建立 NWRCE 作为主题互动中心对于持续开展至关重要。 成功实现 NIAID 和国家传染病议程的规划目标。 该地区有许多机构与威斯康星大学建立了联系，也拥有强大的实力 微生物学和传染病研究项目，包括许多参与和 与 NWRCE 合作的机构包括 Fred Hutchinspn 癌症研究中心、 儿童医院和地区医疗中心、系统生物学研究所、PATH、传染病研究所 疾病研究所和西雅图生物医学研究所（包含 NIAID 资助的 与 NWRCE 合作的结构生物学中心）等其他重要机构。 该地区的传染病研究项目包括 NIAID 的落基山实验室、 太平洋西北国家实验室（包含 NIAID 资助的蛋白质组学中心）、 阿拉斯加州、爱达荷州和俄勒冈州、俄勒冈健康科学中心、俄勒冈州立大学、蒙大拿州 这些机构中的大多数在过去五年中都得到了资助。 蒙大拿州的调查人员最初是通过 NWRCE 资助的，然后是通过 NWRCE 资助的。 成为落基山 RCE 的既定组成部分（David Pascual 博士）。 Guillemen）。太平洋西北地区（特别是西雅图）也是美国的中心之一。 生物技术公司，其中许多专注于传染病和炎症研究，包括 Amgen（原 Immunex） NWRCE 地区的地理位置对于生物防御也具有独特的重要意义。 和新出现的传染病，因为它位于美国西北海岸，与 加拿大，作为通往亚洲的交通门户，这个由 NWRCE 相关机构组成的独特群体。 为 NWRCE 奠定了强大的资源基础。此外，NWRCE 还建立了重要的资源基础。 开展国际合作，以促进其在病原体多样性特征方面的基于疾病的活动 在泰国、瑞典和墨西哥设立中心，与 NWRCE 调查人员合作 类鼻疽、兔热病、肠道疾病和其他新出现的革兰氏阴性细菌传染病的项目。 作为该隶属关系网络的中心枢纽以及传染病研究的领导者， NWRCE 准备继续提升其作为革兰氏阴性菌领域世界领导者的地位 发病机制、免疫反应和治疗开发，并培养下一代 这一重要领域的研究人员。 持续开展主要针对革兰氏阴性菌的计划是有充分理由的。 以下是革兰氏阴性菌应成为研究重点的几个原因。 细菌具有共同的表面结构，具有由两个周质空间隔开的两个膜。 生物防御议程上的 NIAID 分类 A 类病原体是革兰氏阴性细菌，大多数细菌也是如此 B 类病原体的人类感染很容易通过吸入获得。 和口服摄入，这两种途径都可以轻松用于革兰氏阴性细菌的生物攻击。 抗生素耐药性正在增加，与革兰氏阳性菌相比，制药公司已经 这些生物体的药物开发渠道很少。许多革兰氏阴性细菌也是病原体。 此外，革兰氏阴性菌作为重要的植物病原体，可用于攻击食物源。 细菌也对粮食作物构成重大威胁，无论是作为自然出现的病原体还是作为 多年来，人们一直利用多种肠道和呼吸道疾病作为生物恐怖主义的媒介。 作为生物武器，因为它们的稳定性、武器化的潜力以及它们可以轻松地 在《生物危害》一书中，作者肯·阿利贝克描述了前苏联的基因工程。 生物武器计划，重点针对革兰氏阴性生物土拉热杆菌、鼠疫耶尔森菌、鼠疫杆菌、 假鼻疽、鼻疽布鲁氏菌和流产布鲁氏菌 [1] 描述了两类布鲁氏菌的发展。 转基因生物：新的抗生素抗性菌株，以及通过包含而变得更具毒性的菌株 后者的一个例子涉及添加 8. 假鼻疽毒素。 随着使用革兰氏阴性细菌的“超级生物武器”的开发，土拉菌的基因已经被开发出来。 事实上，需要扩大我们关于独特毒力因子和病理学的知识基础 革兰氏阴性菌尤为紧迫，革兰氏阴性菌 Y. 此外，鼠疫菌 (YP) 和 F. tularensis (FT) 是该提案的主要研究焦点。 作为东南亚（西北地区）流行的一种未被充分研究的病原体的重要性 作为运输门户）及其在生物攻击中的可能用途，B 类剂 B. 假鼻疽 (BP)（以及密切相关的鼻疽病菌 B Mallei，BM）也将成为该研究的研究重点 NWRCE。 对革兰氏阴性菌（例如 ¿）的研究cpli、Salmpnellae 和 Yersinia spp. 已被鉴定。 重要的保守结构元件和毒力机制。 细菌含有保守分子，如脂多糖、鞭毛蛋白和脂肽，它们会刺激先天的 细菌还包含操纵或调节这些免疫反应的保守机制。 通过调节 LPS 和鞭毛蛋白等分子的结构和合成并传递 这些生物体还具有保守的抵抗机制。 通过宿主先天免疫效应分子（例如抗菌肽和氧化应激）杀死。 细菌具有保守的毒力蛋白分泌机制 然而，每种病原体都有其独特的酶活性。 这些特性的补充，并且这两种细菌之间存在巨大的生物多样性， 不断进化，而人类的进化部分是由细菌病原体和 因此，必须产生更多的知识，特别是当前的知识。 因此，该提案的重点是病原体。 了解革兰氏阴性细菌的基本和独特的生物学，重点关注这些尚未研究的细菌 具有国家重要性的生物。 尽管 YP、FT 和 BP 有一些共同特征，都是感染细菌的革兰氏阴性病原体。 尽管它们都能够抵抗哺乳动物的先天免疫攻击，但它们也有重要的区别。 在疾病中，YP 和 FT 具有相对非炎症性 LPS 结构 [2, 3]，而 BP 则具有炎症性。 YP 抑制吞噬作用 [4]，而 FT 和 BP 通过液泡裂解从吞噬溶酶体逃逸，其中 它们激活细胞质先天免疫监视途径 [5]。 系统作为致病策略 [6, 7]，而 FT 使用 II 型分泌系统 [8]。 [8]而BP基因组较大，与铜绿假单胞菌和伯克霍尔德氏菌关系更密切 9-11] FT 和 YP 通过昆虫媒介传播 [9, 11]，并存在于小型哺乳动物水库中。 美国和世界各地试图将黑雪貂重新引入蒙大拿州的野生地区。 2007年夏季，鼠疫耶尔森氏菌传播受到野生啮齿动物的限制，而野生啮齿动物是雪貂的主要食物 BP 在整个东南亚都有植物和环境水库[10]。 为了国家安全，必须了解这些水库中生物的多样性也很重要。 了解人类对这些生物体的多样性的本质，以便在国家 可以设定紧急优先事项并制定策略，利用针对我们的化合物 自身的免疫系统可以对抗传染病。 虽然存在 FT 和 YP 疫苗，但这些疫苗无法预防吸入性疾病 [12， 13] NWRCE 在最后一个项目期间开发了早期候选疫苗来应对这些问题。 NWRCE 在上一个项目中开发了候选治疗药物。 通过增强先天免疫，可能对这些病原体具有广谱功效的时期 NWRCE 将增加对这些反应的基本生物学知识。 重要的传染原，并将这些信息转化为广泛应用的疫苗和化合物 在发生生物攻击和/或自然发生的爆发时有用的谱疗法。 NWRCE 研究人员在革兰氏阴性细菌研究和先天免疫方面的独特资格 回应为该提案的重点提供了额外的理由。