PROTECTIVE ROLE FOR NITRIC OXIDE IN AIRWAY INFLAMMATION

描述(由申请人提供)： 这是对为期5年的指导研究培训奖的修订申请，该奖项是为允许候选人发展为职业学术调查员而量身定做的。已注意解决审查员的具体关切。修订后的申请中一个关键的改进是增加了吴琳博士作为联合导师。吴琳博士是国际公认的上皮细胞生物学专家，是指导候选人的理想人选。与吴博士一起指导的开发将集中在特定目标4中令人兴奋的新目标。 加州大学戴维斯分校是应聘者进行这一培训的绝佳环境。它是一个进步的肺部生物学研究中心，医学院、兽医学院和生物科学学院备受尊敬的科学家之间有着独特的互动。除了吴博士，候选人还将继续培养他与他的主要导师杰罗德·拉斯特博士的牢固关系，拉斯特博士是胶原蛋白生物化学和肺纤维化方面的专家。拉斯特博士将自己的专业知识应用于一个共同感兴趣的领域--呼吸道炎症和纤维化--的新问题。一个由加州大学戴维斯分校其他资深科学家组成的咨询委员会将确保候选人的成功，这些科学家在氧化损伤(卡罗尔·克罗斯博士)、肺形态测量(肯特·平克顿博士)和生理学(马克·考夫曼博士)方面具有专业知识。 候选人将研究一氧化氮如何保护呼吸道免受卵白蛋白诱导的呼吸道炎症、纤维化和高反应性的影响。在之前的工作中，候选人和他的导师发现，与C57BL/6小鼠相比，暴露于卵清蛋白4周的NOS2(-L-)小鼠出现了更多的呼吸道胶原沉积和更高的气道反应性。这一建议的具体目的包括：1)确定NOS2来源的NO是否通过影响Th1/Th2淋巴细胞群和/或炎症细胞的凋亡来保护气道高反应性和气道纤维化， 2)建立(在嵌合体NOS2(-L-)x NOS2(+/+)小鼠中)NOS2的主要来源是呼吸道上皮细胞；3)确定NOS1(-L-)和NOS3(-L-)小鼠是否会出现NOS2(-L-)品系中出现的慢性卵蛋白暴露所致的气道纤维化和高反应性增强；以及4)确定在NOS2(-L-)小鼠的气道上皮细胞中插入外部可调节的tet可诱导的NOS2构建体是否可以防止抗原暴露后的呼吸道结构和生理变化。该项目将加强对一氧化氮与气道高反应性和气道纤维化之间关系的理解。此外，它将为候选人在这些领域建立一个专门的专业领域，作为成功的学术生涯的框架。

DESCRIPTION (provided by applicant): This is a revised application for a 5-year Mentored Research Training Award that is tailored to allow the candidate to develop as a career academic investigator. Care has been taken to address the specific concerns of the reviewers. One key improvement in the revised application is the addition of Dr. Reen Wu as a co-mentor. Dr. Reen Wu is an internationally recognized expert in epithelial cell biology and is ideally suited to mentor the candidate. Mentored development with Dr. Wu will focus around an exciting new goal in Specific Aim 4. The University of California, Davis is an outstanding environment for the candidate to pursue this training. It is a center of progressive lung biology research with unique interactions between highly regarded scientists in the Schools of Medicine, Veterinary Medicine, and Biological Sciences. In addition to Dr. Wu, the candidate will continue to foster his strong relationship with his primary mentor, Dr. Jerold Last, an expert in collagen biochemistry and lung fibrosis. Dr. Last has applied his expertise to novel questions in an area of joint interest, airway inflammation and fibrosis. An advisory committee consisting of additional senior UC Davis scientists with expertise in oxidant injury (Dr. Carroll Cross), lung morphometry (Dr. Kent Pinkerton), and physiology (Dr. Marc Kaufman), as well as expert external faculty, will ensure the success of the candidate. The candidate will investigate how nitric oxide protects the airway against ovalbumin-induced airway inflammation, fibrosis and hyperreactivity. In prior work, the candidate and his mentor have found that NOS2 (-l-) mice exposed to ovalbumin for 4 weeks developed increased airway collagen deposition and increased airway responsiveness compared to C57BL/6 mice. The specific aims in this proposal include: 1) Determining whether NOS2-derived NO protects against airway hyperresponsiveness and airway fibrosis by affecting the Th1/Th2 lymphocyte population and/or apoptosis of inflammatory cells, 2) Establishing (in chimera NOS2 (-l-) x NOS2 (+/+) mice) that the predominant NOS2 source is the airway epithelial cells, 3) Determining whether NOS1 (-l-) and NOS3 (-l-) mice develop the enhanced airway fibrosis and hyperresponsiveness in response to chronic ovalbumin exposure seen in the NOS2 (-l-) strain, and 4) Determining whether the insertion of an externally regulatable tet-inducible NOS2 construct into the airway epithelial cells of NOS2-l- mice can prevent the airway structural and physiological changes following antigen exposure. This project will enhance the understanding of the relationship between nitric oxide and airway hyperresponsiveness and airway fibrosis. Moreover, it will establish a niche of expertise in these areas for the candidate that will serve as the framework for a successful academic career.