Thematically, our interdisciplinary PPG proposal, which has undergone significant revision, explores novel molecular mechanisms to inhibit human airway smooth muscle (HASM) contraction and promote bronchodilation. The principal hypothesis states that G protein-coupled receptor (GPCR) desensitization and unbiased signaling limit efficacy of conventional bronchodilators. Targeting these mechanisms will provide improved therapy for asthma. In Project 1, the mechanism by which steroids deter chronic B2-adrenergic receptor (B2AR) tachyphylaxis to 3-agonists will characterize GPCR kinase (GRK)-mediated desensitization and resensitization of the B2AR. Project 2 will advance the recent discovery of bitter taste receptors (TAS2Rs) as novel bronchodilators clarifying the role of TAS2R subtypes in ASM, their mode of regulation and means to improve their efficacy through biased agonism. In Project 3, systematic approaches to characterize the modes of B2AR and Gq-coupled receptor regulation in ASM will be defined to target GRK and arrestin regulation of B2AR desensitization and biased B2AR activation using allosteric modulators or inhibitors of Gq-coupled receptor signaling to protect against pro-contractile mediators. In Project 4, the function and regulation ofthe putative proton-sensing OGR1 in modulating ASM function will be defined, and ligands and regulatory strategies discovered to bias pleiotropic signaling of OGR1 toward pro-relaxant pathways. The four projects will be supported by Core A that will use high through-put screening of small molecule libraries, whole genome, pooled shRNA libraries and virtual screening approaches to identify targets and effectors of bronchodilation. Core B will provide all de-identified human cell and tissue models to study novel mechanisms regulating E-C coupling in HASM. Core C will provide administrative support for the program. This PPG will deliver: an improved understanding of GPCR desensitization in HASM, identify unique molecules that promote Gq-dependent bronchodilation, define novel agonists to TAS2Rs and antagonists to OGR1 to prevent bronchoconstriction.
| Chaturvedi, Madhu; Schilling, Justin; Beautrait, Alexandre et al. (2018) Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors. Trends Biochem Sci 43:533-546 |
| Tliba, Omar; Panettieri Jr, Reynold A (2018) Paucigranulocytic asthma: Uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol : |
| Pera, Tonio; Deshpande, Deepak A; Ippolito, Michael et al. (2018) Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB J 32:862-874 |
| Ojiaku, Christie A; Cao, Gaoyuan; Zhu, Wanqu et al. (2018) TGF-?1 Evokes Human Airway Smooth Muscle Cell Shortening and Hyperresponsiveness via Smad3. Am J Respir Cell Mol Biol 58:575-584 |
| Kennedy, Joshua L; Koziol-White, Cynthia J; Jeffus, Susanne et al. (2018) Effects of rhinovirus 39 infection on airway hyperresponsiveness to carbachol in human airways precision cut lung slices. J Allergy Clin Immunol 141:1887-1890.e1 |
| Komolov, Konstantin E; Benovic, Jeffrey L (2018) G protein-coupled receptor kinases: Past, present and future. Cell Signal 41:17-24 |
| Lapadula, Dominic; Farias, Eduardo; Randolph, Clinita E et al. (2018) Effects of Oncogenic G?q and G?11 Inhibition by FR900359 in Uveal Melanoma. Mol Cancer Res : |
| Lotvall, Jan; Panettieri Jr, Reynold A (2018) Thank you and farewell after 15 years editing respiratory research. Respir Res 19:232 |
| Panettieri, Reynold A; Pera, Tonio; Liggett, Stephen B et al. (2018) Pepducins as a potential treatment strategy for asthma and COPD. Curr Opin Pharmacol 40:120-125 |
| Lo, Dennis; Kennedy, Joshua L; Kurten, Richard C et al. (2018) Modulation of airway hyperresponsiveness by rhinovirus exposure. Respir Res 19:208 |
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