A genetic predisposition to the development of asthma along with exposure to environmental factors such as allergens are required for the development of clinical symptoms. Airway hyperresponsiveness, airway inflammation, and elevated serum IgE are integral components of the asthma phenotype. Abhr1(lod=4.2) and Abhr2(lod=3.7) are quantitative genes that control susceptibility to airway hyperresponsiveness in the progeny of inbred mouse strains(A/J and C3H/HeJ) with significantly different susceptibilities to allergen-induced airway hyperresponsiveness. These genes are located on murine chromosome 2 near the genes for GATA-3 and interleukin-1 receptor antagonist. GATA-3 is essential for Th2-driven inflammation and has been shown to be increased in the airways of asthmatics. Interleukin (IL-1) is a potent proinflammatory cytokine and has been implicated in chronic diseases, including asthma. Thus, based on compelling evidence for linkage and relevant mechanisms of action, we hypothesize that genes encoding GATA-3 and/or interleukin-1 receptor antagonist contribute to allergen-induced airway hyperresponsiveness in our murine model. The overall objective of the current study is to understand the molecular mechanisms that cause airway hyperresponsiveness. The investigators will fine map the location of the gene(s) causing allergen-induced airway hyperresponsiveness in our mouse model by refining quantitative associations between allergen-induced airway responsiveness and DNA marker genotypes using crosses between A/J and C3H/HeJ mice. They will investigate the role of positional candidate genes for antigen-induced airway hyperresponsiveness by 1) determining polymorphisms in genes encoding GATA-3 and interleukin-1 receptor antagonist; 2) determining whether these polymorphisms result in altered message or protein levels, and lastly determining whether polymorphisms are associated with allergen-induced airway hyperresponsiveness via consegregation and functional studies. The results of these studies may lead to better prevention and treatment of asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065469-04
Application #
6619603
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (01))
Program Officer
Banks-Schlegel, Susan P
Project Start
2000-08-05
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
4
Fiscal Year
2003
Total Cost
$317,342
Indirect Cost
Name
Michigan State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Li, Xingnan; Fleis, Rebekah I; Shubitowski, Dennis M et al. (2007) Fine mapping of murine asthma quantitative trait loci and analyses of Ptgs1 and Mrc1 as positional candidate genes. DNA Seq 18:190-5
Li, X; Wills-Karp, M; Ewart, S (2006) Investigating Gata3 as a positional candidate gene for allergic asthma in a murine model. Int J Immunogenet 33:333-7
Shubitowski, D M; Wills-Karp, M; Ewart, S L (2002) The complement factor 5a receptor gene maps to murine chromosome 7. Cytogenet Genome Res 97:133-5