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.
|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|
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