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.

Public Health Relevance

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

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Dong, Gang
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University of Missouri-Columbia
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Amatya, Nilesh; Childs, Erin E; Cruz, J Agustin et al. (2018) IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a. Sci Signal 11:
Chen, Jing; Adamiak, William; Huang, Ganlei et al. (2017) Interaction of RNA-binding protein HuR and miR-466i regulates GM-CSF expression. Sci Rep 7:17233
Chen, Jing; Martindale, Jennifer L; Cramer, Carole et al. (2017) The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells. J Biol Chem 292:14532-14543
Techasintana, Patsharaporn; Ellis, Jason S; Glascock, Jacqueline et al. (2017) The RNA-Binding Protein HuR Posttranscriptionally Regulates IL-2 Homeostasis and CD4+ Th2 Differentiation. Immunohorizons 1:109-123
Techasintana, Patsharaporn; Davis, J Wade; Gubin, Matthew M et al. (2015) Transcriptomic-Wide Discovery of Direct and Indirect HuR RNA Targets in Activated CD4+ T Cells. PLoS One 10:e0129321
Miller, Daniel L; Davis, J Wade; Taylor, Kristen H et al. (2015) Identification of a human papillomavirus-associated oncogenic miRNA panel in human oropharyngeal squamous cell carcinoma validated by bioinformatics analysis of the Cancer Genome Atlas. Am J Pathol 185:679-92
Chen, Jing; Cascio, Jason; Magee, Joseph D et al. (2013) Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR is required for initiation of experimental autoimmune encephalomyelitis. J Immunol 191:5441-50
Dahm, Garrett M; Gubin, Matthew M; Magee, Joseph D et al. (2012) Method for the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts using RIP-Chip. J Vis Exp :
Stellato, Cristiana; Gubin, Matthew M; Magee, Joseph D et al. (2011) Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR. J Immunol 187:441-9
Gubin, Matthew M; Calaluce, Robert; Davis, J Wade et al. (2010) Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis. Cell Cycle 9:3337-46