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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI065566-06
Application #
8196415
Study Section
Special Emphasis Panel (ZRG1-RES-C (02))
Program Officer
Dong, Gang
Project Start
2010-07-01
Project End
2011-12-31
Budget Start
2010-07-01
Budget End
2010-12-31
Support Year
6
Fiscal Year
2010
Total Cost
$205,928
Indirect Cost
Name
Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Martinez, Luis R; Boucaud, Dwayne W; Casadevall, Arturo et al. (2018) Factors Contributing to the Success of NIH-Designated Underrepresented Minorities in Academic and Nonacademic Research Positions. CBE Life Sci Educ 17:ar32
Pabon, Jonathan; Law, Man Kit; August, Avery (2017) Drebrin Regulation of Calcium Signaling in Immune Cells. Adv Exp Med Biol 1006:281-290
Huang, Weishan; August, Avery (2016) Role(s) of IL-2 inducible T cell kinase and Bruton's tyrosine kinase in mast cell response to lipopolysaccharide. Genom Data 8:18-20
Huang, Weishan; Morales, J Luis; Gazivoda, Victor P et al. (2016) Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide. J Allergy Clin Immunol 137:1197-1205
Kannan, Arun; Lee, YongChan; Qi, Qian et al. (2015) Allele-sensitive mutant, Itkas, reveals that Itk kinase activity is required for Th1, Th2, Th17, and iNKT-cell cytokine production. Eur J Immunol 45:2276-85
Law, Mankit; Lee, YongChan; Morales, J Luis et al. (2015) Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses. J Immunol 195:426-30
Huang, Weishan; Qi, Qian; Hu, Jianfang et al. (2014) Dendritic cell-MHC class II and Itk regulate functional development of regulatory innate memory CD4+ T cells in bone marrow transplantation. J Immunol 192:3435-3441
Huang, Weishan; Jeong, Ah-Reum; Kannan, Arun K et al. (2014) IL-2-inducible T cell kinase tunes T regulatory cell development and is required for suppressive function. J Immunol 193:2267-72
Huang, Weishan; Morales, J Luis; Gazivoda, Victor P et al. (2013) The zinc-binding region of IL-2 inducible T cell kinase (Itk) is required for interaction with G?13 and activation of serum response factor. Int J Biochem Cell Biol 45:1074-82
Kannan, Arun K; Sahu, Nisebita; Mohanan, Sunish et al. (2013) IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-? in naive CD4+ T cells. J Allergy Clin Immunol 132:811-20.e1-5

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