The mouse asthma model core (scientific core C) will coordinate and perform the experiments in projects 2, 3 and 4 that involve the mouse asthma model. In Project 4, the Leader, Dr. Spiegel, has developed specific inhibitors for sphingosine-1-kinase and will use these in an inhalent model to get them directly to the lung. This largely avoids systemic toxicity and targets the affected organ directly. The concept being tested is whether inhibition of lung mast cells is sufficient to inhibit the asthma model. In addition, the program director will use siRNA to block, in vivo, in lung the synthesis of sphingosine kinase in order to determine whether this will inhibit asthma development. In Project 2, Dr. Conrad has demonstrated that overexperssion of CD23 inhibits IgE production and eosinophil recruitment to the lung. Experiments will be performed to determine if IgE is necessary for the eosinophil recruitment. In addition, the CD23 sheddase has been identified as ADAM 10 and siRNA knock-down experiments will be performed in collaboration with Dr. Spiegel to determine if blockade of ADAM10 in the lung, either by siRNA or specific inhibitors influences asthma development and symptoms. In Project #3, Dr. Ryan is examining the allergic phenotype of lyn knockout animals with the objective of determining the activities of lyn in the mast cell. The lyn[-/-] mice are known to develop severe Th2 disease including increased IgE and eosinophil responses. These activities, not surprisingly, lead to a severe asthma phenotype. In collaboration with Dr, Conrad, the lyn[-/-] animals will be crossed to CD23 transgenics to see if the Th2 disease is modulated. In addition, the activities of ADAM10 inhibitors either via a siRNA or chemical inhibitor methodology, introduced directly into the lung, will be tested for capacity to modulate the lyn[-/-] severe Th2 disease modality. In all of these studies, the core will provide the expertise to both perform and analyze data from the mouse asthma model. These include maintenance of mice for the 30 day period required for sensitization, aerosol challenge and ultimate sacrifice with BAL fluid collection and lung preparation for histology and RNA analysis.
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