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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL114471-01A1
Application #
8476658
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Banks-Schlegel, Susan P
Project Start
2013-07-15
Project End
2018-06-30
Budget Start
2013-07-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$2,365,675
Indirect Cost
$812,651
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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