Pulmonary Pathogen-Recognition Pathways in Melioidosis

简介(申请人提供)：韦斯特博士的职业目标是成为一名物理学家，精通肺宿主防御机制的翻译研究，重点研究细菌呼吸道感染，这是世界各地发病率和死亡率的主要原因。这一职业发展应用程序描述了具有两个主要目标的综合课程。第一个目标是为候选人提供深入的肺部生物学和免疫学知识，并扩大实验室方法的培训，以促进其职业发展走向独立。第二个目标是确定类鼻疽病的肺部病原体识别途径，类鼻疽病是一种由假鼻疽伯克霍尔德氏菌引起的致命热带感染，是一种潜在的气溶胶生物武器。韦斯特博士的职业发展计划包括讲授课程，参加科学研讨会和会议，教授实验室实用技能，与华盛顿大学和海外的多学科科学家小组密切合作，由一名经验丰富的高级研究员进行密集指导，以及由学术咨询委员会进行监督。这项研究计划结合了各种各样的基因敲除小鼠、各种原代细胞的体外研究、复杂的空气传播疾病小鼠模型，以及获得专门的实验室设施。该建议的具体目的是：1)在体外鉴定Toll样受体(TLRs)-跨膜病原体识别传感器-及其下游信号通路，以介导假鼻疽识别；2)确定TLR信号通路在肺炎类鼻炎中影响固有免疫和获得性免疫的特定成分；以及3)确定胞浆ICE-蛋白酶激活因子(IPAF)/caspase-1信号轴在类鼻疽病中的相关作用。在进行这些研究时，韦斯特博士将受到著名研究员肖恩·斯克雷特博士的密切监督，他的研究重点是利用小鼠疾病模型研究细菌性肺炎的先天免疫。韦斯特博士还将与一个由微生物学家、免疫学家和病理学家组成的杰出团队合作，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分享特定的专业知识。华盛顿大学科学家拥有丰富的学术和物质资源，为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项目的综合优势将极大地促进韦斯特博士朝着他的职业目标前进。相关性(见说明)：这项研究直接涉及美国国立卫生研究院宣称的使命，即追求基础科学知识，以减少疾病和残疾的负担。这些研究将增加我们对致命的细菌感染类鼻疽病的了解，这是一个日益严重的公共卫生问题，并可能最终导致这种疾病的新治疗方法的开发。这些发现也可能适用于其他呼吸道感染--全球范围内对穷人影响不成比例的主要死亡和残疾原因。

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.