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 i n 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL076415-05
Application #
7662350
Study Section
Special Emphasis Panel (ZHL1-CSR-M (O1))
Program Officer
Rothgeb, Ann E
Project Start
2005-09-26
Project End
2010-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$123,405
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Bratt, Jennifer M; Franzi, Lisa M; Linderholm, Angela L et al. (2009) Arginase enzymes in isolated airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin. Toxicol Appl Pharmacol 234:273-80

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