Asthma affects millions of people worldwide and has been gaining prevalence in the US. Symptoms of allergic asthma include airway inflammation, increased numbers of eosinophils in BAL and sputum, and airways hyperresponsiveness. While the role of eosinophils in regulating the development and/or symptoms of allergic asthma is controversial, it is clear that they play some role in this disease. A proper understanding of the role of these cells in modulating the development and/or severity of allergic asthma will allow us to have an impact on this disease. Our long-range goal is to provide a detailed understanding of the role of eosinophils in allergic airway responses. The objective of this application is to determine eosinophil functions that may modulate the development of airway inflammation and airways hyperresponsiveness during allergic airway responses. The proposed experiments arose from our preliminary data and are driven by a central hypothesis, that eosinophils modulate airway production of chemokines, altering T cell recruitment to the lung and elaboration of their effector function during the development of allergic airway inflammation. Our rationale is that a better understanding of the role of eosinophil function in this disease will provide us with information needed to treat diseases such as allergies and asthma. We plan 3 specific aims: 1) determine the role of eosinophils in inducing airway inflammation and AHR during the development and maintenance of airway allergic responses, 2) determine whether eosinophil derived Th2 cytokines are required for the recruitment of CD4+ T cells into the lung and the development of allergic airway response;and 3) Determine role of eosinophil derived factors in modulating the elaboration of Th2 effector function during airway allergic responses. The proposed work is innovative, and we are well poised to conduct these studies because we will be taking advantage of knockout and transgenic mouse models to perform these experiments. We expect that our approach will identify the role of eosinophils 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 eosinophils that may be used to manipulate their functions involved in asthma. PROJECT NARRATIVE: Asthma is an increasingly prevalent disease in the US and other developing countries. Eosinophils 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 eosinophils 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 eosinophils 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 #
5R01AI073955-06
Application #
8278687
Study Section
Special Emphasis Panel (ZRG1-RES-C (03))
Program Officer
Minnicozzi, Michael
Project Start
2008-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$372,420
Indirect Cost
$127,395
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; 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
August, Avery; Ragin, Melanie J (2012) Regulation of T-cell responses and disease by tec kinase Itk. Int Rev Immunol 31:155-65
Walsh, Elizabeth R; August, Avery (2010) Eosinophils and allergic airway disease: there is more to the story. Trends Immunol 31:39-44
Sahu, Nisebita; August, Avery (2009) ITK inhibitors in inflammation and immune-mediated disorders. Curr Top Med Chem 9:690-703
Walsh, Elizabeth Rose; Sahu, Nisebita; Kearley, Jennifer et al. (2008) Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma. J Exp Med 205:1285-92