Cytoprotective Effect of CO in Lung Ischemia/Reperfusion

描述(由申请人提供)： 这份提案描述了一个指导科学培训和职业发展的5年计划，目标是成为一名成功的独立临床科学家。这位首席研究员已经完成了研究生培训，并在他所关注的肺移植领域取得了显著的临床地位。在这样做的同时，他一直保持着积极和富有成效的研究，包括有效的合作。他现在希望扩大他的科学能力，成为一名独立的研究员，并以一种有意义的方式为基本了解肺移植的病理生理学做出贡献。 科学训练将集中在肺损伤和一氧化碳(CO)的影响上。奥古斯丁·崔博士将指导首席研究员，蒂莫西·比利亚尔博士将担任联合导师。崔博士是肺内科主任，发表了大量关于一氧化碳的文章，而蒂莫西·比利亚尔博士是外科主任，发表了大量关于一氧化氮(NO)的文章。两者都培养了许多成功的临床科学家。一个顾问委员会将由崔博士和比利亚博士以及著名外科科学家理查德·西蒙斯博士组成。CO和NO专业知识的集中是相当独特的，大学内良好的研究环境和该系培养成功的外科科学家的广泛记录也是如此。 研究和培训将集中在CO在肺缺血/再灌注(I/R)损伤中的细胞保护作用。崔博士实验室的研究表明，一氧化碳具有强大的抗炎、抗凋亡和抗增殖特性。最近与首席研究员和崔博士的合作表明，在与人类移植相关的肺I/R损伤模型中，CO通过其抗凋亡作用提供细胞保护，并表明HSP70可能介导了这些作用。我们建议进一步研究CO在肺I/R中的细胞保护作用，并提出新的假设，即CO通过p38途径激活应激反应基因HSP70来调节抗凋亡作用。其具体目的包括：1)确定CO对肺热I/R和冷I/R损伤的影响；2)确定CO在体外和体内激活HSP70的机制；3)确定CO在体外和体内诱导HSP70激活的功能意义。

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.