Asthma affects millions of people worldwide and is gaining prevalence in the U.S. with the greatest increase seen among inner city African Americans and Hispanics. The reasons for this increase are not well understood, but may be the result of a complex interplay of genetic, socio-economic, behavioral, and environmental factors. Patients with allergic asthma manifest airway inflammation, and some show hallmarks of a classic Th2 response and airway hyperresponsiveness. This Th2 type response points to a prominent role for these cells and their cytokines in the pathology of this disease. An understanding of the development of these cells will allow us to develop approaches to prevent or decrease the severity of this disease. Our long-range goal is to provide a detailed understanding of Th2 cell development, and the effect of Th2 cells and their cytokines on allergic asthma. In pursuit of that goal, the objective of this renewal application is to continue to determine the role of Itk in T cell subset differentiation and cytokine production in the development of allergic asthma. The central hypothesis is that Itk regulates the development of specific T cell subsets, contributing to the development of allergic asthma. Our rationale is that a better understanding of Th2 cell development and cytokine production 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 the development of T cell subsets;2) Determine the role of Itk in chemokine receptor function;and 3) Determine the role of Tec kinase signals in regulating allergic airway inflammation. The proposed work is innovative, and we are well poised to conduct these studies because we will be taking advantage of mouse genetic systems lacking various Tec kinases or mutant forms of these kinases. This information 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 specific T cell functions involved in allergy and asthma. PROJECT NARRATIVE. Asthma is an increasingly prevalent disease in the US and other developing countries. T helper 2 cells and cytokines are present in the airways of patients with this disease. The work proposed in this application is highly relevant and significant as we expect to identify the role of Tec kinases in modulating the development of airway inflammation and airways hyperresponsiveness. 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 within T cells that may be used to manipulate their functions involved in asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051626-11
Application #
8237038
Study Section
Special Emphasis Panel (ZRG1-RES-C (02))
Program Officer
Dong, Gang
Project Start
2002-12-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
11
Fiscal Year
2012
Total Cost
$362,582
Indirect Cost
$117,557
Name
Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Huang, Weishan; Huang, Fei; Kannan, Arun Kumar et al. (2014) ITK tunes IL-4-induced development of innate memory CD8+ T cells in a ?? T and invariant NKT cell-independent manner. J Leukoc Biol 96:55-63
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 192:3435-41
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
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-ýý in naive CD4+ T cells. J Allergy Clin Immunol 132:811-20.e1-5
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
Huang, Weishan; Hu, Jianfang; August, Avery (2013) Cutting edge: innate memory CD8+ T cells are distinct from homeostatic expanded CD8+ T cells and rapidly respond to primary antigenic stimuli. J Immunol 190:2490-4
August, Avery; Ragin, Melanie J (2012) Regulation of T-cell responses and disease by tec kinase Itk. Int Rev Immunol 31:155-65
Qi, Qian; Huang, Weishan; Bai, Yuting et al. (2012) A unique role for ITK in survival of invariant NKT cells associated with the p53-dependent pathway in mice. J Immunol 188:3611-9
Law, Mankit; Morales, J Luis; Mottram, Laurie F et al. (2011) Structural requirements for the inhibition of calcium mobilization and mast cell activation by the pyrazole derivative BTP2. Int J Biochem Cell Biol 43:1228-39
Qi, Qian; Xia, Mingcan; Bai, Yuting et al. (2011) Interleukin-2-inducible T cell kinase (Itk) network edge dependence for the maturation of iNKT cell. J Biol Chem 286:138-46

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