The candidate, David W. Kaczka, MD, PhD is an Assistant Professor of Anesthesiology and Critical Care Medicine at the Johns Hopkins University. His long-term career goal is to become an independent scientist conducting translational research in pulmonary physiology. To accomplish this goal, he has developed this proposal outlining a 4-year, multi-disciplinary training program designed to develop the academic career of a biomedical engineer and anesthesiologist. The long-term objective of this project is to develop noninvasive techniques for optimizing mechanical ventilation in patients with acute lung injury (ALI). The hallmark of All is its mechanical heterogeneity, resulting in repetitive intratidal end-expiratory airway closure and end-inspiratory alveolar overdistention during positive pressure ventilation. This causes further lung injury and poor outcomes in patients. Since the nature and degree of .mechanical heterogeneity depend on lung volume, we have hypothesized that ventilating over pressure ranges which minimize heterogeneity can be useful for optimizing therapy in patients and reducing ventilator-associated lung injury (VALI). Thus, the proposed studies will characterize the nature and distribution of regional heterogeneity in injured canine lungs using both functional lung imaging and respiratory mechanical impedance (Zrs). Emphasis will be placed on evaluating the potential of Zrs to provide a real-time, noninvasive assessment of mechanical heterogeneity to allow for the development of individualized ventilation protocols in patients. Specfic Aim 1 will use CT-based 3D image registration to determine how the regional mechanics of the injured lung vary with lung volume. Specific Aim 2 will validate estimates of mechanical heterogeneity inferred from Zrs to those obtained by functional lung imaging. Finally, Specific Aim 3 will develop an optimized, lung protective ventilation strategy based on Zrs, and assess its impact on mechanical heterogeneity and surrogate outcome markers of VALI. Public Health Relevance: By making such measurements in a canine model of ALI, we will evaluate the potential of both CT image registration as well as Zrs to provide specific information regarding the regional mechanical heterogeneity of injured lungs. This will allow for the development of better ventilation protocols in patients with ALI, which will have the potential to minimize the risk of injurious ventilation and reduce its associated mortaility.