Cytoprotective Effect of CO in Lung Ischemia/Reperfusion

描述（由申请人提供）： 该提案描述了一个5年的指导科学培训和职业发展计划，目标是成为一名成功的独立临床科学家。 主要研究者已完成研究生培训，并在其关注的领域肺移植的短时间内取得了显著的临床地位。 在这样做的同时，他保持了积极和富有成效的研究，包括有效的合作。 他现在希望扩大自己的科学能力，成为一名独立的研究者，并以有意义的方式对肺移植的病理生理学的基本理解做出贡献。 科学的训练将侧重于肺损伤和一氧化碳（CO）的影响。 Augustine Choi博士将指导主要研究者，Timothy Billiar博士将担任共同导师。 Choi博士是肺内科主任，并发表了大量关于CO的文章，而Timothy Billiar博士是外科主任，并发表了大量关于一氧化氮（NO）的文章。 他们都培养了许多成功的临床科学家。 一个咨询委员会将由崔博士和比利亚尔博士以及著名的外科科学家理查德·西蒙斯博士组成。 CO和NO专业知识的集中是非常独特的，因为大学内的优秀研究环境和该部门培训成功的外科医生科学家的广泛记录。 研究工作和培训将集中在CO在肺缺血/再灌注（I/R）损伤中的细胞保护作用。 Choi博士实验室的工作表明，CO具有有效的抗炎，抗凋亡和抗增殖特性。 最近与主要研究者和Choi博士的合作表明，CO通过其在与人类移植相关的肺I/R损伤模型中的抗凋亡作用提供细胞保护，并表明HSP 70可能介导这些作用。 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HSP 70来调节抗凋亡作用。 具体目标包括：目的1）研究CO对肺热I/R和冷I/R损伤的影响; 2）研究CO在体内外激活HSP 70的机制; 3）研究CO在体内外激活HSP 70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.