The overall goal of this AADCRC application is to understand how innate and adaptive immune signals contribute to the pathogenesis of asthma and thereby develop new therapeutic strategies for this condition. We give special emphasis to the initiation and termination of both antiviral and allergic responses as critical elements in asthma, and we use isolated cell and mouse models with high fidelity to directly translate our findings to humans. The AADRC therefore consists of three interrelated Projects that address first, how the asthmatic condition may be initiated at the level of the innate immune response in the airway epithelium (Project 1), second, how these innate signals may subsequently trigger an inhibitory immune response via complement system components interacting with T regulatory (Treg) cells (Project 2), and third, how additional inhibitory signals in the adaptive immune system may ultimately shut off the immune and inflammatory process (Project 3). Thus, Project 1 focuses on how airway epithelial cells achieve a proper balance of IFN-driven Stat1 signals to achieve optimal antiviral defense and so prevent the acute and chronic development of asthma traits. The Project tests this proposal experimentally by engineering deficiency versus hyper-responsiveness of Stat1 signaling in transgenic mice, and then uses the same biomarkers to study this balance during the development of asthma in children with viral infection. Project 2 uses the same mouse model of viral bronchiolitis as well as allergen challenge to determine how specific components of the complement system may contribute to the innate response while other components provide a signal for the development of Treg cells that dampen the antiviral and allergic responses. Project 3 continues the theme for immune balance and the proposition that a deficiency in turning off the immune response could lead to an excessive and prolonged inflammatory response to allergic and other stimuli. This Project takes advantage of its discovery of a new inhibitory receptor (BTLA) in the context of other similar receptors (PD-1) and corresponding ligands to define the influence of these inhibitory signals on the allergic response in mice. In turn, each Project (1, 2, and 3) will validate and extend its findings using samples from adult patients with established asthma. Overlapping scientific goals create a synergistic program that can be supported by a common set of cores: the Administrative Core will coordinate the activities of the AADCRC and will provide computer and statistical support. The Human Subjects Core will recruit children and adults as research subjects, obtain clinical research materials, and assure uniformity among clinical protocols. The Morphology Core provides for tissue processing and analysis. The Mouse Core develops new transgenic mice and provides facilities for physiologic measurements of airway function. Project and Core interactions are based on the overall principle that each Project begins with molecular hypothesis building in isolated-cell and mouse models and translates findings from these models to studies of children and adults with asthma.
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