Immunomodulatory Effects of Mechanical Ventilation

描述(由申请人提供)： 这份提案描述了一项为期五年的培训计划，旨在培养一名肺部和重症监护医学领域的内科科学家。首席研究员已完成临床培训，并具有肺生理学领域的研究经验。拟议的培训计划的目标是提供必要的技能，将细胞机制的研究与整个器官的生理反应结合起来。这一目标将通过讲授教育和精心设计的研究计划相结合来实现，该计划由肺部生理学领域的专家Robb Glenny博士和基因转录的细胞调控途径专家Karol Bomsztyk博士指导。该研究计划将重点放在机械通风作为急性肺损伤(ALL)发生发展的辅助因素中的作用。机械通气策略决定了ALL患者的存活率；然而，它在ALL发病机制中的作用和所涉及的细胞通路都不清楚。拟议的实验将使用脓毒症的兔模型来评估机械通气促进肺损伤的近端机械刺激和末端效应通路。由于肿瘤坏死因子-α是炎症的主要介质，实验将特别关注由肿瘤坏死因子配体-受体结合引起的主要细胞反应途径：核因子-kappaB核转位和启动caspase级联反应。具体目标包括：1)量化机械通气对内毒素介导的肺损伤发展的影响；2)量化不同机械通气策略对内毒素介导的肺损伤的区域性发展的影响；3)评估机械通气对内毒素血症时核因子-kappaB活化的影响4)评估机械通气对内毒素血症时caspase介导的细胞死亡的影响这项应用利用华盛顿大学医学系现有的多样性资源，为首席研究人员提供独特的培训计划，旨在促进专注于综合肺生理学的成功研究生涯。

DESCRIPTION (provided by applicant): This proposal describes a five-year training program for the development of a physician-scientist in the field of Pulmonary and Critical Care Medicine. The principal investigator has completed clinical training and has research experience in the field of pulmonary physiology. The objective of the proposed training program is to provide the skills necessary to integrate the study of cellular mechanisms with whole organ physiologic response. This objective will be achieved through the combination of didactic education and a carefully designed research program mentored by Dr. Robb Glenny, an expert in the field of pulmonary physiology, and Dr. Karol Bomsztyk, and expert in cellular regulatory pathways of gene transcription. The research program will focus on the role of mechanical ventilation as a co-factor in the development of acute lung injury (ALl). Mechanical ventilation strategy determines survival in patients with ALl; however, neither its role in the pathogenesis of ALl nor the cellular pathways involved are known. The proposed experiments will use a rabbit model of sepsis to evaluate both the proximal mechanical stimulus and the end-effector pathway by which mechanical ventilation promotes lung injury. Because TNF-alpha is a principal mediator of inflammation, experiments will look specifically at the major cellular response pathways that result from TNF ligand-receptor binding: NF-kappaB nuclear translocation and initiation of the caspase cascade. Specific aims include: 1) Quantifying the effect of mechanical ventilation on the development of endotoxin-mediated lung injury; 2) Quantifying the effect of different mechanical ventilation strategies on the regional development of endotoxin-mediated lung injury; 3) Evaluating the effect of mechanical ventilation on NF-kappaB activation during endotoxemia 4) Evaluating the effect of mechanical ventilation on caspase-mediated cell death during endotoxemia This application takes advantage of the diversity of resources available within the Department of Medicine at the University of Washington to provide the principal investigator with a unique training program designed to foster a successful research career focused on integrative pulmonary physiology.