Asthma has been increasing in prevalence and severity for unknown reasons. Though our understanding of the pathophysiology remains poor, it is widely accepted that asthma is an inflammatory disease and CD4+ T cells elaborating Th2 cytokines have been identified as major culprits in its development. Many of these genes are posttranscriptionally regulated but their regulation is not well understood. We have developed a new paradigm, the posttranscriptional operon hypothesis, which states that RNA binding proteins are coordinately regulating the expression of biologically related molecules. Our hypothesis is that the RNA binding protein, HuR, is coordinately regulating Th2 polarization and cytokine gene expression in allergic airway inflammation. HuR is a major stabilizer of labile mRNAs containing AU rich instability elements (AREs) in their 3'untranslated regions. All the Th2 cytokines and 90% of cytokines and chemokines have AREs. 1. Determine effects of HuR modulation upon Th2 polarization and cytokine production in lymphocytes. We will employ lentiviral vectors to under-express HuR in CD4+ T cells and assay Th1/Th2 polarization and cytokine gene expression. 2. Determine role of HuR over-expression and under-expression in murine models of allergic airway inflammation. We will test whether altering HuR levels will modify asthma development in animal models of allergic airway inflammation. 3. Does HuR mediated allergic inflammation involves microRNAs? We will isolate and identify microRNAs from lungs of ova sensitized animals using arrays. Our approach will provide a fuller understanding of the identity and regulation of proinflammatory genes involved in asthma. Better understanding of proinflammatory gene regulation at the posttranscriptional level may potentially lead to targeted therapies to treat asthma.
The reasons for the increasing incidence and prevalence of allergies and asthma worldwide are presently unknown. Exciting new discoveries in posttranscriptional gene regulation and microRNAs potentially may have broad impacts on our understanding of allergen driven asthma.
The aim of this proposal is to better understand how cytokine genes are regulated at the posttranscriptional level. This would greatly aid in our understanding of disease pathogenesis and treatment and have a direct impact on public health. PHS 398/2590 (Rev. 09/04) Page 15 Continuation Format Page
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