Allergic asthma is a chronic disorder with rising incidence. The pathogenesis of asthma is complex and multifactorial. However, common to the various phenotypic patterns of asthma is the presence of underlying airway inflammation. An important first step toward developing improved approaches to asthma diagnosis, treatment, and prevention is to understand the molecular pathogenesis of the disease. MicroRNAs are a class of small non-coding RNAs that repress the expression of protein-coding genes. While microRNAs have been reported to mediate the pathogenesis of diverse diseases, the role of miRNA in the pathogenesis of asthma is virtually unknown, expect for a couple of early recent reports. Preliminary data demonstrate miR-21 as one of the most up-regulated miRNA in allergic asthma models, and provide evidence that miR-21 regulates IL12p35 expression in vitro, possibly affecting the balance of Th1 vs Th2 vs Th17 response. The severity of asthma is often correlated with the level of airway eosinophilia. Correspondingly, miR-21 has been found to be up- regulated stepwise during eosinophil development. The long-term objective of the present work is to elucidate the involvement of miR-21 in the pathogenesis of asthma with the goal of developing novel approaches to disease diagnosis, treatment and prevention. We hypothesize that miR-21 is central to the pathogenesis of allergic asthma, affecting the balance of Th1 vs Th2 vs Th17 responses, as well as the development, recruitment and function of eosinophils.
Aim one in this proposal is designed to elucidate the role of miR-21 in the development and function of eosinophils. Anti-miR-21 treated cells will be compared with control cells to determine the involvement of miR-21 in cellular proliferation, differentiation, maturation and function in an eosinophil culture system.
Aim two in this proposal will determine whether the up-regulation of miR-21 contributes to exaggerated Th2 response and asthma remodeling in vivo. Cytokine production, airway inflammation and airway remodeling in experimental asthma will be measured in miR-21 knockout mice compared to wildtype littermate controls. Collectively, the results from these studies will provide a better understanding of the function of miR-21 in asthma pathogenesis. Elucidating the function of specific microRNAs in asthma pathogenesis may lead to the development of novel small RNA based therapies for the treatment of this ever-increasing disease.

Public Health Relevance

More than 300 million people suffer from asthma worldwide. The involvement of microRNAs represents a new dimension in the pathogenesis of this complex and multifactorial disease. This proposal aims to elucidate the function of miR-21 in the pathogenesis asthma. These studies are expected to improve understanding of the molecular pathogenesis of asthma thereby facilitating development of novel approaches to treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Tigno, Xenia
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University of Cincinnati
Internal Medicine/Medicine
Schools of Medicine
United States
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Lu, Thomas X; Lim, Eun-Jin; Itskovich, Svetlana et al. (2013) Targeted ablation of miR-21 decreases murine eosinophil progenitor cell growth. PLoS One 8:e59397
Lu, Thomas X; Rothenberg, Marc E (2013) Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. J Allergy Clin Immunol 132:3-13; quiz 14
Lu, Thomas X; Lim, Eun-Jin; Besse, John A et al. (2013) MiR-223 deficiency increases eosinophil progenitor proliferation. J Immunol 190:1576-82
Lu, T X; Lim, E-J; Wen, T et al. (2012) MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome. Mucosal Immunol 5:388-96
Lu, Thomas X; Sherrill, Joseph D; Wen, Ting et al. (2012) MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol 129:1064-75.e9
Lu, Thomas X; Hartner, Jochen; Lim, Eun-Jin et al. (2011) MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity. J Immunol 187:3362-73