PROTECTIVE ROLE FOR NITRIC OXIDE IN AIRWAY INFLAMMATION

描述（由申请人提供）： 这是一个5年的指导研究培训奖，是量身定制的，让候选人发展为职业学术研究者的修订申请。 对审议者的具体关切已作了认真处理。 修订后的应用程序的一个关键改进是增加了Reen Wu博士作为共同导师。 Reen Wu博士是国际公认的上皮细胞生物学专家，非常适合指导候选人。 与吴博士一起指导的开发将专注于具体目标4中令人兴奋的新目标。 加州大学戴维斯分校是一个优秀的环境，为候选人追求这一培训。 它是一个先进的肺生物学研究中心，在医学，兽医和生物科学学院备受推崇的科学家之间有着独特的互动。 除了吴博士，候选人将继续培养他与他的主要导师，博士杰罗尔德最后，在胶原蛋白生物化学和肺纤维化的专家牢固的关系。 Last博士将他的专业知识应用于共同感兴趣的气道炎症和纤维化领域的新问题。 一个咨询委员会，由额外的高级加州大学戴维斯分校科学家与专业知识在氧化损伤（卡罗尔十字），肺形态（肯特平克顿博士），和生理学（马克博士考夫曼），以及专家外部教师，将确保候选人的成功。 研究一氧化氮如何保护气道免受卵白蛋白诱导的气道炎症、纤维化和高反应性。 在先前的工作中，候选人和他的导师发现，与C57 BL/6小鼠相比，暴露于卵白蛋白4周的NOS 2（-l-）小鼠的气道胶原沉积增加，气道反应性增加。 1）确定NOS 2衍生的NO是否通过影响Th 1/Th 2淋巴细胞群和/或炎性细胞的凋亡来防止气道高反应性和气道纤维化， 2)建立（在嵌合体NOS 2（-1-）x NOS 2（+/+）小鼠中），主要的NOS 2来源是气道上皮细胞，3）确定NOS 1（-1-）和NOS 3（-1-）小鼠是否发展出在NOS 2（-1-）品系中观察到的响应于慢性卵清蛋白暴露的增强的气道纤维化和高反应性，和4）确定将外部可调节的tet诱导型NOS 2构建体插入NOS 2 - 1-小鼠的气道上皮细胞中是否可以防止抗原暴露后的气道结构和生理变化。 本研究将增进对一氧化氮与气道高反应性及气道纤维化关系的了解。 此外，它将为候选人在这些领域建立一个专门知识的利基，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.