Pulmonary Pathogen-Recognition Pathways in Melioidosis

类鼻疽中的肺部病原体识别途径

基本信息

批准号：
8014917
负责人：
Timothy Eoin West
金额：
$ 12.74万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8014917
关键词：
Adaptor Signaling Protein Address Advisory Committees Aerosols Alveolar Macrophages Antibiotic Therapy Antibody Formation Bacteria Bacterial Infections Bacterial Pneumonia Biology Blocking Antibodies Bone Marrow Breathing Burkholderia pseudomallei Caspase-1 Categories Cause of Death Cell Death Cells Centers for Disease Control and Prevention (U.S.)Collaborations Communicable Diseases Complex Cytochalasin D Dendritic Cells Dendritic cell activation Development Development Plans Disease Disease model Dose Educational Curriculum Environment Enzymes Epithelial Cells Flagellin Genes Goals Histopathology Host Defense Host Defense Mechanism Host resistance Immune Immune response Immunoglobulin G Immunoglobulin M Immunologist Immunology In Situ Nick-End Labeling In Vitro Individual Infection Inflammatory Response Instruction Interleukin-1 Interleukin-18 Investigation Knockout Mice Knowledge Laboratories Lead Ligands Lipopolysaccharides Lung Mastigophora Measures Mediating Melioidosis Mentorship Methods Mission Modeling Morbidity - disease rate Multiprotein Complexes Mus Natural Immunity Natural Killer Cells Nuclear Nuclear Translocation Pathologist Pathway interactions Phenotype Pneumonia Population Principal Investigator Process Production Public Health Receptor Signaling Research Research Personnel Resources Respiratory Tract Infections Role Scientist Sepsis Serum Signal Pathway Signal Transduction Splenocyte TLR2 gene TLR4 gene TLR5 gene TdT-Mediated dUTP Nick End Labeling Assay Testing Toll-like receptors Training United States National Institutes of Health Universities Washington Western Blotting adaptive immunity aerosolized alveolar bone bacterial genetics burden of illness career career development cytokine cytosolic receptor cytotoxicity disability global health laboratory facility macrophage mortality multidisciplinary novel therapeutics pathogen programs receptor response sensor skills symposium translational study uptake

项目摘要

DESCRIPTION (provided by applicant): Dr. West's career goal is to become a physican-scientist proficient in the translational study of mechanisms of pulmonary host defense, with a focus on bacterial respiratory infections, major causes of morbidity and mortality around the world. This career development application describes an integrated curriculum with two main objectives. The first objective is to provide the candidate with an in-depth knowledge of lung biology and immunology, and expanded training in laboratory methods to facilitate his career development toward independence. The second objective is to define pulmonary pathogen-recognition pathways in melioidosis, a lethal tropical infection caused by Burkholderia pseudomallei, a potential aerosol bioweapon. Dr. West's career development plan comprises didactic coursework, participation in scientific seminars and conferences, instruction in practical laboratory skills, close collaborations with a multidisciplinary group of scientists at University of Washington and abroad, intensive mentorship by an accomplished senior investigator, and oversight by an academic advisory committee. The research plan combines a wide assortment of gene knockout mice, in vitro studies of a variety of primary cells, sophisticated murine models of airborne disease, and access to specialized laboratory facilities. The specific aims of this proposal are: 1) to identify Toll-like receptors (TLRs) - transmembrane pathogen-recognition sensors - and downstream signaling pathways that mediate recognition of B. pseudomallei in vitro; 2) to define TLR signaling pathways in pneumonic melioidosis that influence specific components of innate and adaptive immunity; and 3) to determine the related role of the cytosolic ICE-protease-activating factor (IPAF)/caspase-1 signaling axis in melioidosis. In performing these studies, Dr. West will be closely supervised by Dr. Shawn Skerrett, a distinguished investigator whose research focus is the investigation of innate immunity in bacterial pneumonias using murine models of disease. Dr. West will also collaborate with an outstanding team of microbiologists, immunologists, and pathologists who share specific expertise in host-pathogen interactions, host and bacterial genetics, and mouse pneumonia models. The extensive academic and physical resources available to University of Washington scientists create an ideal environment for this career development training. Furthermore, the combined strengths of University of Washington's pulmonary, infectious diseases, and global health research programs will greatly facilitate Dr. West's progression toward his career goal. RELEVANCE (See instructions): This research directly addresses the stated mission of the NIH to pursue fundamental scientific knowledge that reduces the burden of illness and disability. These studies will increase our understanding of the lethal bacterial infection melioidosis, a growing public health problem, and may ultimately lead to the development of new treatments for this disease. The findings may also be applicable to other respiratory infections - leading causes of death and disability worldwide that disproportionately impact the poor.

描述（由申请人提供）：韦斯特博士的职业目标是成为熟练的物理学家，精通肺部宿主防御机制的转化研究，重点是细菌呼吸道感染，世界范围内发病和死亡率的主要原因。该职业发展应用程序描述了一个具有两个主要目标的集成课程。第一个目标是为候选人提供有关肺部生物学和免疫学的深入了解，并扩大了实验室方法的培训，以促进他的职业发展实现独立性。第二个目标是定义黑梅利病中的肺病原体识别途径，这是由Burkholderia pseudomallei引起的致命的热带感染，这是潜在的气溶胶生物武器。韦斯特博士的职业发展计划包括教学课程，参加科学研讨会和会议，实践实验室技能的指导，与华盛顿大学和国外的多学科科学家进行密切合作，由一位有成就的高级研究员进行强化指导以及学术咨询委员会的监督。该研究计划结合了各种基因基因敲除小鼠，对各种原始细胞的体外研究，空气疾病的复杂鼠模型以及进入专业实验室设施的通道。该提案的具体目的是：1）鉴定Toll样受体（TLR） - 跨膜病原体识别传感器 - 以及下游信号通路，以介导对体外假单胞菌的识别； 2）定义肺炎黑胶质病中的TLR信号传导途径，以影响先天和适应性免疫的特定组成部分； 3）确定胞质冰蛋白酶激活因子（IPAF）/caspase-1信号轴在Melioidosis中的相关作用。在进行这些研究时，West博士将由杰出研究者Shawn Skerrett博士密切监督，其研究重点是使用鼠类疾病模型对细菌性肺炎的先天免疫进行研究。 West博士还将与杰出的微生物学家，免疫学家和病理学家团队合作，他们在宿主 - 病原体相互作用，宿主和细菌遗传学以及小鼠肺炎模型方面具有特定的专业知识。华盛顿大学科学家可用的广泛的学术和物理资源为这项职业发展培训创造了理想的环境。此外，华盛顿大学的肺部，传染病和全球健康研究计划的综合优势将极大地促进韦斯特博士朝着他的职业目标发展。相关性（请参阅说明）：这项研究直接解决了NIH的既定任务，以追求减轻疾病和残疾负担的基本科学知识。这些研究将提高我们对致命细菌感染黑脂蛋白病的理解，这是一个日益增长的公共卫生问题，并最终可能导致对这种疾病的新疗法发展。这些发现也可能适用于其他呼吸道感染 - 世界范围内的死亡和残疾的主要原因会对穷人产生不成比例的影响。