This a new project that has the goal of identifying novel mechanisms of asthma pathogenesis, as well as new treatment approaches for patients with severe disease. The project will utilize murine models of allergic asthma to achieve these goals. The three main objectives of this project are as follows: 1. To identify microRNAs in the lung that regulate airway inflammation and remodeling in allergic asthma. microRNAs are small, regulatory RNAs that are transcribed from distinct genes and can bind to multiple mRNAs and either suppress translation or target mRNAs for destruction. We have identified microRNAs from lungs of asthmatic and non-asthmatic mice using microRNA expression profiling and have validated their expression using real-time quantitative PCR. Candidate microRNAs will be selected to generate transgenic animals that conditionally over-express microRNAs in airway epithelial cells or other cell types. In addition, knock-out and/or conditional knock-out mice will be created to assess the effect of deletion of these microRNAs on the pathogenesis of asthma. These models will be used to assess the role of microRNAs in regulating airway inflammation and remodeling in asthma. 2. To explore the role of immunoregulatory exosomes in attenuating airway inflammation and remodeling responses in allergic asthma. Prior studies have shown that tolerogenic dendritic cells, which have immunosuppressive properties, can prevent the rejection of transplanted organs (Morelli AE, et al, Nat Rev Immunol 2007, 7:610) and protect against allergic airway inflammation in mice (Fujita S., J Allergy Clin Immunol 2007, epublished). A concern regarding the administration of live dendritic cells, however, is that they may either lose their immunosuppressive properties or become immunostimulatory. An alternative approach is to collect exosomes from immature dendritic cells that have tolerogenic or immunoregulatory properties. These tolerogenic or immunoregulatory exosomes should retain the immunosuppressive properties of dendritic cells and may be administered as a therapy for asthma. The ability of immunoregulatory exosomes to attenuate airway inflammation and remodeling will be assessed in murine models of allergic asthma. 3. To assess the utility of new treatment approaches for allergic asthma, such as multi-target tyrosine kinase receptor antagonists. These experiments will assess the efficacy of new therapeutic approaches for severe asthma in murine models of allergic asthma. Therapies that are effective in pre-clinical models can then be considered candidates for future clinical trials involving asthmatic patients. Experiments will assess whether receptor tyrosine kinase inhibitors, such as sorafenib, represent effective treatment options for patients with severe asthma. Sorafenib is a multi-target kinase inhibitor that targets pathways that are relevant for airway inflammation and remodeling in asthma, such as c-Raf-1, VEGFR, PDGRFR, c-Kit, (and possibly p38 MAP kinase). We propose that sorafenib may attenuate both asthmatic airway inflammation (mediated by eosinophils, neutrophils and mast cells), as well as airway remodeling manifested by airway smooth muscle hyperplasia and vasculogenesis. Inhibition of the Ras/Raf/MEK/ERK pathway in murine models of allergic asthma by either over-expression of an enzymatically inactive Ras in T cells or by administration of the MAPK/ERK inhibitor, U0126, has been shown to inhibit cardinal manifestations of allergic asthma, including Th2 cytokine production, eosinophilic airway inflammation, serum IgE, mucus production, and airway hyperreactivity (J Immunol 2002;169: 2134 2140, J Immunol 2004;172: 7053 7059). Furthermore, Ras has been shown to mediate eosinophil survival and airway epithelial cell mucin gene expression (Blood 2001;98: 2014 2021, J Mol Biol 2004;344: 683-695). Raf-1 mediates neutrophil chemotaxis (JCI 1994;94: 815 823), as well as inhibits apoptosis of vascular endothelial cells (Science 2003;301: 94 96) and neutrophils (Cellular Signaling 2004;16: 801 810). Similarly, ERK1/2 has been shown to mediate airway smooth muscle proliferation (Am J Physiol Lung Cell Mol Physiol 2001;280: L1019 L1029). Other important targets of sorafenib for the treatment of asthma are VEGF receptors and c-Kit. VEGF signaling has been shown to induce an asthma-like phenotype in the mouse, characterized by airway inflammation, vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia, subepithelial fibrosis, and airway hyperreactivity (Nat Med 2004;10: 1095 1103). Furthermore, mast cells are required for the full development of airway hyperreactivity, mucus hyperproduction, collagen deposition, and airway inflammation (JCI 2006;116: 1633 1641).
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