Asthma affects millions of people worldwide and is gaining prevalence in the U.S. Patients with allergic asthmahave symptoms of airway inflammation, with eosinophilia, increased mucous production in the lung and serumIgE, along with airway hyper responsiveness. While the role of IgE in regulating allergic asthma is controversial,it is clear that airway exposure to allergen can lead to early phase airway hyperresponsiveness. This is due toantigen specific IgE mediated activation of mast cells via their high affinity Fc Receptor for IgE (FcepsilonRI),resulting in degranulation and pharmacological effects on lung smooth muscle cells. While much is known aboutthe signaling pathway used by the FcepsilonRI, there are still gaps in the knowledge as to how this receptorfunctions. A proper understanding of the activation of mast cells via the FcepsilonRI will allow us to developapproaches that will have an impact on the development and or severity of allergic airway as well as other allergicresponses. Our long-range goal is to provide a detailed understanding of Itk in allergic airway responses. Inpursuit of that goal, the objective of this application is to determine the role of Itk in mast cell function duringallergic airway responses. The central hypothesis is that Itk regulates mast cell activation by the high affinityFcepsilonR, contributing to the development of airway allergic responses. Our rationale is that a betterunderstanding of the role of Itk in mast cell function and activation will provide us with information needed torationally design methods to treat diseases such as allergies and asthma. We will test our hypothesis by pursuingthe following three specific aims: 1) Determine the role of Itk in regulating early FcepsilonRI signaling in mastcells, 2) Determine the role of Itk in regulating pro- and anti-inflammatory cytokine production induced byFcepsilonRI in mast cells and 3) Determine the role of Itk in regulating mast cell function in vivo during airwayallergic responses. The proposed work is innovative, because we will be taking advantage of knockout andtransgenic mouse models lacking Itk, Btk, Itk and Btk, or mast cells to perform these experiments. We expect thatour approach will identify the role of Itk in regulating mast cell activation and function by FcepsilonRI in vivo.The data generated from this application will have a significant impact on human health, as we expect to provideinformation on the molecular pathology of asthma, and on potential targets such as Itk that may be used tomanipulate mast cell specific functions involved in allergy and asthma.
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