This is the first revision of a proposal by a New Investigator to look at potential genetic abnormalities that may predispose individuals to asthma. The cytokine IL-4 has been shown to be important in the development of many asthmatic lesions. IL-4 binds to the IL-4 receptor alpha (IL-4Ra). This group previously has described a novel allele of IL-4Ra in which Arg replaces glutamine at position 576. This allele, named the R576 IL-4Ra allele, correlates with a ninefold increase in atopy risk, and is also associated with increased IL-4 responsiveness. There are now at least five additional polymorphic variants of IL-4Ra, and the purpose of this application is to determine the effects of each of the IL-4Ra variants, alone and in combination, on IL-4 responsiveness and the asthmatic phenotype in humans. The applicants propose to introduce missense mutations for each of the IL-4Ra alleles into the human IL-4Ra cDNA, and to transfect them into murine B cells. They then will analyze the transfectants with respect to IL-4 sensitivity and temporal responsiveness to IL-4, specifically related to activation of STAT6 and expression of CD23. They then wish to genotype a cohort of well-characterized asthmatic patients and to identify the specific IL-4Ra alleles as markers of asthma risk or severity. Finally, they wish to look at STAT6 activation and CD23 expression in A202.1 murine B cells, as used in the first aim, after cotransfection with combinations of the different allelic variants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI046652-01A1
Application #
6193938
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Plaut, Marshall
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$259,000
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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