We propose to use a mouse model of allergen induced airway remodeling to investigate the contribution of? mast cells to airway remodeling, as well as to understand the mechanism by which mast cell progenitors? traffic from the bone marrow to the lung and contribute to airway remodeling. In particular we hypothesize? that mast cell derived TNF plays a central role in mediating allergen induced airway remodeling through? effects on airway smooth muscle, as well as through recruitment of mast cell progenitors and eosinophils to? the lung. To test this hypothesis we plan to determine levels of allergen induced airway remodeling in WT? mice and compare this to levels noted in mutant mice (mast cell deficient, TNF deficient), as well as mast? cell deficient mice reconstituted with TNF deficient mast cells. In addition, we have utilized cre/lox molecular? techniques to generate mice deficient in the ability to activate NF-kB in airway epithelium. As these mutant? mice exhibit reduced numbers of peribronchial mast cells, they will be utilized to investigate the role of NFkB? regulated genes in airway epithelium contributing to mast cell progenitor trafficking to the remodeled? airway. Overall, these studies will provide insight into the mechanism by which mast cell derived TNF? contributes to airway remodeling, as well improve our understanding of the mechanism by which NF-kB? regulated genes in airway epithelium direct mast cell progenitor trafficking from the bone marrow to the lung? and contribute to airway remodeling.? TNF is a protein that is highly expressed in the airway in asthmatics with ongoing symptoms of asthma. Our? studies in a mouse model will shed light on whether therapies targeting TN in asthma may provide a novel? strategy to reduce airway scarring in severe asthmatics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-03
Application #
7684687
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$198,136
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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White, Andrew A; Doherty, Taylor A (2018) Role of group 2 innate lymphocytes in aspirin-exacerbated respiratory disease pathogenesis. Am J Rhinol Allergy 32:7-11

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