Our renewal of this interdisciplinary PPG remains focused on the theme of novel molecular mechanisms to inhibit human airway smooth muscle (HASM) contraction and promote bronchodilation within the context of airway inflammation and asthma. The principal hypothesis states that G protein coupled receptor (GPCR) desensitization and unbiased signaling limits the efficacy of conventional bronchodilators, such that targeting desensitization mechanisms, promoting biased agonism, circumventing mechanisms of ASM hypercontractility/airway hyperresponsiveness (AHR), or engaging novel bronchorelaxant mechanisms in HASM will provide superior therapy for asthma. Each Project addresses this hypothesis by either: 1) optimizing pro- relaxant signaling abilities of one of 3 different GPCRs using strategies rooted in cutting edge biophysical or pharmacological approaches; or 2) establishing novel intracellular targets mediating inflammation-driven AHR and increased GPCR pro-contractile signaling. Project 1 will establish the mechanisms by which TGF-?1 modulates excitation-contraction (EC) coupling of HASM and thereby identify novel therapeutic targets linked to both AHR and increased GPCR-mediated contraction. Project 2 will advance the recent discovery of bitter taste receptors (TAS2R) as novel bronchodilators clarifying the role of TAS2R subtypes in HASM, their mode of regulation and means to improve their efficacy through biased agonism. Project 3 will characterize the molecular basis of ?2AR biased signaling to develop compounds that mediate Gs-biased signaling through either inhibition of ?-arrestin interaction with the agonist-occupied ?2AR (arrestin-biased negative allosteric modulators (NAMs)) or by enhancing coupling of the ?2AR to Gs (biased orthosteric agonists). Project 4 will similarly characterize the mechanisms underlying biased signaling of OGR1, develop new biased OGR1 benzodiazepine derivatives with superior ability to bronchodilate, and determine the relative contribution of and mechanisms underlying peripheral benzodiazepine receptor activation by candidate drugs. 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 EC coupling in HASM. Core C will provide administrative support for the program. The strengths of this Program are the common focus on a single theme and the productive working relationship among investigators with the ability to apply cutting edge GPCR biology to key questions in asthma biology and pharmacology.
The overarching goal of this program project grant (PPG) is to bridge gaps in our understanding of asthma physiology and treatment by defining new targets and therapies that block or reverse bronchoconstriction. This application for a Supplement to Promote Diversity in Health-Related Research seeks to take advantage of successful inter-project/core collaboration, which has uncovered a novel target for improved treatment of asthma. This diversity supplement will provide critical staffing to leverage an emerging research opportunity while simultaneously providing an ideal training project for the candidate.
| 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 |
| Kim, Donghwa; Cho, Soomin; Woo, Jung A et al. (2018) A CREB-mediated increase in miRNA let-7f during prolonged ?-agonist exposure: a novel mechanism of ?2-adrenergic receptor down-regulation in airway smooth muscle. FASEB J 32:3680-3688 |
| Huang, Yapei; Xie, Yan; Jiang, Haihong et al. (2018) Upregulated P-Rex1 exacerbates human airway smooth muscle hyperplasia in asthma. J Allergy Clin Immunol : |
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