Asthma affects millions of people worldwide and is gaining prevalence in the U.S. Patients with allergic asthma have symptoms of airway inflammation, with eosinophilia, increased mucous production in the lung and serum IgE, 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 to antigen specific IgE mediated activation of mast cells via their high affinity Fc Receptor for IgE (Fc(RI), resulting in degranulation and pharmacological effects on lung smooth muscle cells. While much is known about the signaling pathway used by the Fc(RI, there are still gaps in the knowledge as to how this receptor functions. A proper understanding of the activation of mast cells via the Fc(RI will allow us to develop approaches that will have an impact on the development and or severity of allergic airway as well as other allergic responses. Our long-range goal is to provide a detailed understanding of Itk in allergic airway responses. In pursuit of that goal, the objective of this application is to determine the role of Itk in mast cell function during allergic airway responses. The central hypothesis is that Itk regulates mast cell activation by the high affinity Fc(R, contributing to the development of airway allergic responses. Our rationale is that a better understanding of the role of Itk in mast cell function and activation will provide us with information needed to rationally design methods to treat diseases such as allergies and asthma. We will test our hypothesis by pursuing the following three specific aims: 1) Determine the role of Itk in regulating early Fc(RI signaling in mast cells, 2) Determine the role of Itk in regulating pro- and anti-inflammatory cytokine production induced by Fc(RI in mast cells and 3) Determine the role of Itk in regulating mast cell function in vivo during airway allergic responses. The proposed work is innovative, because we will be taking advantage of knockout and transgenic mouse models lacking Itk, Btk, Itk and Btk, or mast cells to perform these experiments. We expect that our approach will identify the role of Itk in regulating mast cell activation and function by Fc(RI in vivo. The data generated from this application will have a significant impact on human health, as we expect to provide information on the molecular pathology of asthma, and on potential targets such as Itk that may be used to manipulate mast cell specific functions involved in allergy and asthma. ? ? ?
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