Cytoprotective Effect of CO in Lung Ischemia/Reperfusion

CO 对肺缺血/再灌注的细胞保护作用

• 批准号: 6759741
• 负责人: KENNETH R. MCCURRY
• 金额: $ 12.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-02 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6759741
• 关键词: apoptosis; carbon monoxide; cytoprotection; disease /disorder model; enzyme activity; gene induction /repression; genetically modified animals; heat shock proteins; heme oxygenase; laboratory mouse; laboratory rat; lung injury; lung ischemia /hypoxia; lung transplantation; reperfusion; tissue /cell culture; vascular endothelium; western blottings

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.

描述（由申请人提供）： 该建议描述了一项为期5年的指导科学培训和职业发展计划，目的是成为成功的独立临床科学家。 首席研究人员已经完成了研究生培训，并在其集中兴趣，肺移植的领域很短的时间内实现了大量的临床地位。 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，成为一名独立研究者，并以有意义的方式为对肺移植的病理生理学的基本理解做出贡献。 科学训练将集中于肺损伤和一氧化碳（CO）的影响。 奥古斯丁·崔（Augustine Choi）博士将指导首席调查员，蒂莫西·台球（Timothy Billiar）博士将担任联合学者。 Choi博士是肺部医学部门的负责人，并在CO上广泛发表，而Timothy Billiar博士是外科部主席，并广泛发表了一氧化氮（NO）。 两者都培训了许多成功的临床科学家。 咨询委员会将由Drs组成。崔和台球以及著名的外科科学家理查德·西蒙斯（Richard Simmons）博士。 CO和NO的专业知识的集中度非常独特，该大学的出色研究环境以及该系的培训成功的外科医生的广泛记录。 研究工作和培训将集中于CO在肺部缺血/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，抗凋亡和抗增殖性质。 最近与主要研究者的合作工作，Choi博士证明，CO通过其在肺I/R损伤模型中通过其抗凋亡效应提供与人类移植有关的抗凋亡作用，并表明HSP70可以介导这些作用。 我们建议进一步检查CO在肺I/R中的细胞保护作用，并提出了新的假设，该假设通过通过p38途径激活应力响应基因HSP70来调节抗凋亡效应。 具体目的包括：目标1）确定CO对肺温暖I/R和冷I/R损伤的影响；目标2）确定CO在体外和体内激活HSP70的机制；目标3）确定在体外和体内共诱导的Hsp70激活的功能意义。