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.
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