We propose to use a mouse model of allergen induced airway remodeling to investigate the contribution ofmast cells to airway remodeling, as well as to understand the mechanism by which mast cell progenitorstraffic from the bone marrow to the lung and contribute to airway remodeling. In particular we hypothesizethat mast cell derived TNF plays a central role in mediating allergen induced airway remodeling througheffects on airway smooth muscle, as well as through recruitment of mast cell progenitors and eosinophils tothe lung. To test this hypothesis we plan to determine levels of allergen induced airway remodeling in WTmice and compare this to levels noted in mutant mice (mast cell deficient, TNF deficient), as well as mastcell deficient mice reconstituted with TNF deficient mast cells. In addition, we have utilized cre/lox moleculartechniques to generate mice deficient in the ability to activate NF-kB in airway epithelium. As these mutantmice exhibit reduced numbers of peribronchial mast cells, they will be utilized to investigate the role of NFkBregulated genes in airway epithelium contributing to mast cell progenitor trafficking to the remodeledairway. Overall, these studies will provide insight into the mechanism by which mast cell derived TNFcontributes to airway remodeling, as well improve our understanding of the mechanism by which NF-kBregulated genes in airway epithelium direct mast cell progenitor trafficking from the bone marrow to the lungand contribute to airway remodeling.TNF is a protein that is highly expressed in the airway in asthmatics with ongoing symptoms of asthma. Ourstudies in a mouse model will shed light on whether therapies targeting TN in asthma may provide a novelstrategy to reduce airway scarring in severe asthmatics.
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