Posttranscriptional Gene Regulation in Asthma

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DESCRIPTION (provided by applicant): 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. Current approaches have emphasized the use of microarrays to define "asthma signature genes". Though these approaches are helpful, they are also incomplete and may miss important target genes since there is a poor correlation between steady-state mRNA levels and protein production. 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, such as those involved in T cell activation. Our central hypothesis is that the RNA binding protein, HuR, is coordinately regulating IL-4 and IL-13 cytokine genes during allergen driven asthma. The RNA binding protein, HuR, binds to the AU-rich elements (ARE) in the 3' untranslated regions (UTR) of mRNAs and modulates their stability and translation. The ARE motif is found in 8% of human genes and plays a critical role in posttranscriptional gene expression. In particular, two major Th2 cytokines, IL- 4 and IL-13, believed to play critical roles in allergen driven asthma, are regulated by HuR at the level of mRNA stability and translation. We have developed novel methods to identify en masse cellular in vivo HuR mRNA targets. Using these approaches, we have identified IL-4 and IL-13 as HuR targets. We will test this hypothesis with the following two specific aims: 1: Examine the effects of HuR modulation in CD4+ T cells upon IL-4 and IL-13 expression. 2: Assess the role of HuR in CD4+ T cells in allergen driven models of asthma in mice. Our approach will provide a fuller understanding of the regulation of proinflammatory cytokine genes involved in allergen driven asthma. Better understanding of proinflammatory gene regulation at posttranscriptional level may potentially lead to targeted therapies to treat asthma. Public Health Relevance: The rise of allergies and asthma around the world continues to perplex physicians and scientists. The reasons for this increase are unknown. Different responses to therapies for asthma are most likely due to differences in genetic backgrounds of patients. A better understanding of asthma pathophysiology at the posttranscriptional gene regulation level would greatly aid in our understanding of disease pathogenesis and treatment and have a direct impact on public health.