Cytoprotective Effect of CO in Lung Ischemia/Reperfusion

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DESCRIPTION (provided by applicant): This proposal describes a 5-year plan of mentored scientific training and career development with the goal of becoming a successful independent clinical-scientist. The principal investigator has completed postgraduate training and has achieved significant clinical standing in a brief period of time in his area of focused interest, lung transplantation. While doing so he has maintained active and productive research including effective collaborations. He now wishes to expand his scientific abilities to become an independent investigator and contribute in a meaningful way to the basic understanding of the pathophysiology of lung transplantation. The scientific training will focus on lung injury and the effect of carbon monoxide (CO). Dr. Augustine Choi will mentor the principal investigator, and Dr. Timothy Billiar will serve as co-mentor. Dr. Choi is Division Chief of Pulmonary Medicine and has published extensively on CO, while Dr. Timothy Billiar is Chairman of the Department of Surgery and has published extensively on nitric oxide (NO). Both have trained numerous successful clinical-scientists. An advisory committee will be composed of Drs. Choi and Billiar as well as Dr. Richard Simmons, a renowned surgical scientist. The concentration of expertise in CO and NO is quite unique as is the excellent research environment within the University and the Department's extensive record of training successful surgeon-scientists. Research efforts and training will focus on the cytoprotective effects of CO in lung ischemia/reperfusion (I/R) injury. Work in Dr. Choi's laboratory has demonstrated that CO has potent anti-inflammatory, anti-apoptotic and anti-proliferative properties. Recent collaborative work with the principal investigator and Dr. Choi has demonstrated that CO provides cytoprotection via its anti-apoptotic effect in models of lung I/R injury that are relevant to human transplantation and suggest that HSP70 may mediate these effects. We propose to further examine the cytoprotective effect of CO in lung I/R and propose the novel hypothesis that CO regulates anti-apoptotic effects by activation of the stress response gene HSP70 via the p38 pathway. The specific aims include: Aim 1) to determine the effect of CO on lung warm I/R and cold I/R injury; Aim 2) to determine the mechanism by which CO activates HSP70 in vitro and in vivo; and Aim 3) to determine the functional significance of CO-induced HSP70 activation in vitro and in vivo.