Reduced airway pH can be caused by exogenous as well as endogenous sources including ainway inflam- mation, and can contribute to the pathophysiology of obstructive airway diseases. Neural mechanisms are known capable of mediating acidosis-induced bronchoconstriction, but whether reduced pH in the ainway microenvironment has direct effects on ainway smooth muscle (ASM) is unknown. We have discovered that ASM expresses 0GR1, a member of a unique subfamily of G protein-coupled receptors (GPCRs) proposed to be "proton-sensing." Preliminary data suggest 0GR1 is expressed in ASM and, in response to reductions in extracellular pH, signals in a manner consistent with pro-contracfile Gq-coupled GPCRs. Moreover, with modest step decreases in buffer pH that parallel the activation of 0GR1, murine tracheal rings contract ex vivo, as do ASM cells from 0GR1 +/+ but not -/- mice. Mindful of the inherent difficulties in invesfigating a receptor whose cognate ligand may be a proton, we have assembled a team of experts in GPCR biology, airway biology, and integrafive models of acid-induced bronchoconstriction to undertake the challenge of: 1) establishing the relevance of 0GR1 to ASM contractility;and 2) idenfifying therapeutic drugs and strategies to manipulate its signaling and funcfion in ASM.
In Aim 1, we propose to detail acid-induced signaling events in ASM, employing both genetic and molecular biology approaches on ASM cells to establish the contribufion, and mechanism of acfivation, of 0GR1.
Aim 2 will validate recently discovered allosteric modulators as agonists/antagonists of CGRI signaling, and take advantage of screening/drug discovery approaches and tools established for this PPG to identify means of antagonizing pro-contracfile signaling while enhancing pro-relaxant signaling.
In Aim 3, we will establish both relevance and robustness of pH- dependent 0GR1 funcfion in ASM by taking advantage of cutting edge models of cell, tissue, and ainway contraction, and utilize drugs/strategies developed in Aim 2 to render OGR1 pro-relaxant as opposed pro- contracfile. Collectively, these studies will help idenfify a novel signaling pathway in ASM that participates in the pathobiology of numerous ainways diseases, and determine a means to target it therapeutically.

Public Health Relevance

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Kim, Won-Keun; Jain, Deepika; Sánchez, Melissa D et al. (2014) Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation. Am J Respir Crit Care Med 189:437-48
Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C et al. (2014) ?-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent. J Biol Chem 289:23065-74
Damera, Gautam; Panettieri, Reynold A (2014) Irreversible airway obstruction in asthma: what we lose, we lose early. Allergy Asthma Proc 35:111-8
Pera, Tonio; Penn, Raymond B (2014) Crosstalk between beta-2-adrenoceptor and muscarinic acetylcholine receptors in the airway. Curr Opin Pharmacol 16:72-81
Kang, Dong Soo; Tian, Xufan; Benovic, Jeffrey L (2014) Role of ?-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63-71
Liggett, Stephen B (2014) Bitter taste receptors in the wrong place: novel airway smooth muscle targets for treating asthma. Trans Am Clin Climatol Assoc 125:64-74; discussion 74-5
Hu, Ruoxi; Pan, Wenchi; Fedulov, Alexey V et al. (2014) MicroRNA-10a controls airway smooth muscle cell proliferation via direct targeting of the PI3 kinase pathway. FASEB J 28:2347-57
Dileepan, Mythili; Jude, Joseph A; Rao, Savita P et al. (2014) MicroRNA-708 regulates CD38 expression through signaling pathways JNK MAP kinase and PTEN/AKT in human airway smooth muscle cells. Respir Res 15:107
Robinett, Kathryn S; Koziol-White, Cynthia J; Akoluk, Arda et al. (2014) Bitter taste receptor function in asthmatic and nonasthmatic human airway smooth muscle cells. Am J Respir Cell Mol Biol 50:678-83
Penn, Raymond B; Bond, Richard A; Walker, Julia K L (2014) GPCRs and arrestins in airways: implications for asthma. Handb Exp Pharmacol 219:387-403

Showing the most recent 10 out of 11 publications