Genome wide association studies have identified strong linkage between chromosome 17q21 and asthma. The focus of this proposal is on ORMDL-3, a protein localized to chromosome 17q21, which has been highly linked to asthma in several genome wide association studies. The investigation of the function of ORMDL-3 in the lung in asthma in this proposal will be enhanced by the development of unique reagents in the investigators lab (e.g. universal and cell specific ORMDL-3 transgenic and ORMDL-3 deficient mice; development of antibody to ORMDL to perform immunohistological). Based on our preliminary data we hypothesize that allergen induced ORMDL-3 expression regulates expression of multiple epithelial pathways (inflammation, remodeling, repair), as well as the ER ATF6 pathway which together play an important role in the pathogenesis of asthma. The studies proposed will use in vitro (knock down or over-expression of ORMDL-3 in lung cells) and in vivo studies (ORMDL-3 transgenic and ORMDL-3 deficient mice) to determine the role of ORMDL3 in the pathogenesis of allergen and rhinoviral induced asthma.
Although the gene ORMDL-3 on chromosome 17q21 is highly associated with the development of asthma, little is known about the function of ORMDL-3 and how it may contribute to the development of asthma. In this study we will use lung cells from mice and humans as well as a mouse model of asthma to determine how ORMDL-3 causes asthma. This may provide insight into novel treatments for asthma.
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