Pulmonary Pathogen-Recognition Pathways in Melioidosis

描述（由申请人提供）：West博士的职业目标是成为一名精通肺部宿主防御机制转化研究的物理学家，重点是细菌性呼吸道感染，这是世界各地发病率和死亡率的主要原因。这个职业发展应用程序描述了一个综合课程，有两个主要目标。第一个目标是为候选人提供肺生物学和免疫学的深入知识，并扩大实验室方法的培训，以促进其独立的职业发展。第二个目标是确定类鼻疽的肺部病原体识别途径，类鼻疽是一种由类鼻疽伯克霍尔德菌（一种潜在的气溶胶生物武器）引起的致命热带感染。West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，指导实际的实验室技能，与华盛顿大学和国外的多学科科学家小组密切合作，由一位有成就的高级研究员进行密集指导，并由学术咨询委员会进行监督。该研究计划结合了各种基因敲除小鼠，各种原代细胞的体外研究，空气传播疾病的复杂小鼠模型，以及使用专门的实验室设施。该提议的具体目标是：1）鉴定Toll样受体（TLR）-跨膜病原体识别传感器-和介导B识别的下游信号传导途径。类鼻疽; 2）确定肺部类鼻疽中影响先天性和适应性免疫的特定组分的TLR信号传导途径;和3）确定胞质ICE-蛋白酶激活因子（IPAF）/半胱天冬酶-1信号传导轴在类鼻疽中的相关作用。在进行这些研究时，West博士将由Shawn Skerrett博士密切监督，Shawn Skerrett博士是一位杰出的研究人员，其研究重点是使用小鼠疾病模型研究细菌性肺炎的先天免疫。West博士还将与一支由微生物学家，免疫学家和病理学家组成的优秀团队合作，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拥有特定的专业知识。华盛顿大学的科学家们拥有广泛的学术和物质资源，为这种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（参见说明）：这项研究直接解决了NIH的既定使命，即追求减少疾病和残疾负担的基础科学知识。这些研究将增加我们对致死性细菌感染类鼻疽的了解，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发展。这些发现也可能适用于其他呼吸道感染--世界范围内对穷人影响不成比例的死亡和残疾的主要原因。

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.