The Interaction of environmental factors with asthma susceptibility genes plays a fundamental role in the genesis and persistence of the asthma epidemic. Particularly important in this process are allelic variants along the IL-4/IL-13/IL-4 receptor axis, which have been linked to distinct asthma phenotypes. Many of the mechanisms by which these alleles exert their functions are unclear, including the proximal signaling events involved, the consequent genetic and epigenetic responses underlying disease chronicity, and their interface with environmental influences in programming allergic diseases. By employing incisive genetic mouse models, we have established a causative link between Il4ra alleles and atopy and asthma. More recently, we have also established that a human polymorphism, IL-4RaQ576R, which associates with severe and fatal/near fatal asthma, enables a novel Stat6-independent pathway involving MAP kinases (MAPKs) that, in synergy with Stat6, promotes severe allergic airway inflammation and remodeling. Our recent studies reveal that IL-13- induced allergic airway inflammation associates with an epigenetic methylation signature that may contribute to inflammation, airway remodeling and disease chronicity. These signaling, genetic and epigenetic events are themselves subject to environmental influences, as revealed by preliminary studies showing synergy between the Il4raR576 allele and diesel exhaust particles (DEP) in allergic inflammation. Based on the above, we hypothesize that severe asthma-associated Il4raR576 allele mobilizes a mechanistically distinct signaling pathway that mediates the allele's exaggerated allergic inflammatory and tissue remodeling attributes. Furthermore, we hypothesize that Il4ra signaling imparts an epigenetic signature that contributes to airway remodeling and disease chronicity. Finally, we hypothesize that DEP act synergistically with Il4raR576 by mechanisms involving the oxidative stress response and the Notch pathway. These hypotheses will be validated using a combination of molecular, cellular and whole animal approaches. Our studies address fundamental attributes of gene/environment interaction in asthma, promise novel insights into disease pathogenesis and chronicity and new approaches to therapy.
Asthma has become a modern epidemic with the alarming rise in its incidence in recent years and tens of millions of individuals in the United States alone suffering its ravages. The mechanisms involved in the rise of its incidence include genetic factors that predispose to allergy, and environmental factors relating to a modern life style, including increased exposure to environmental carbon fuel-related particulate matter (PM) such as diesel exhaust particles (DEP). Our proposed studies examine how human genetic mutations in a major allergy pathway promote disease, and how PM interacts with this pathway to worsen disease outcome. We are particularly interested in so called epigenetic changes in the airways, changes that stably alter the DNA of the airway tissues so that to enable asthma to persist for years even while the original insult has dissipated. Our proposed studies will allow the development of effective tests to predict the severity and chronicity of asthma and novel therapies that reprogram the asthmatic airways into healthy ones.
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