Reduced airway pH can be caused by exogenous as well as endogenous sources including airway inflammation, 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 airway microenvironment has direct effects on airway smooth muscle (ASM) is unknown. We have discovered that ASM expresses OGR1, a member of a unique subfamily of G protein-coupled receptors (GPCRs) proposed to be "proton-sensing." Preliminary data suggest OGR1 is expressed in ASM and, in response to reductions in extracellular pH, signals in a manner consistent with pro-contractile Gq-coupled GPCRs. Moreover, with modest step decreases in buffer pH that parallel the activation of OGR1, murine tracheal rings contract ex vivo, as do ASM cells from OGR1 +/+ but not -/- mice. Mindful of the inherent difficulties in investigating a receptor whose cognate ligand may be a proton, we have assembled a team of experts in GPCR biology, airway biology, and integrative models of acid-induced bronchoconstriction to undertake the challenge of: 1) establishing the relevance of OGR1 to ASM contractility;and 2) identifying therapeutic drugs and strategies to manipulate its signaling and function 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 contribution, and mechanism of activation, of OGR1.
Aim 2 will validate recently discovered allosteric modulators as agonists/antagonists of OGR1 signaling, and take advantage of screening/drug discovery approaches and tools established for this PPG to identify means of antagonizing pro-contractile signaling while enhancing pro-relaxant signaling.
In Aim 3, we will establish both relevance and robustness of pH- dependent OGR1 function in ASM by taking advantage of cutting edge models of cell, tissue, and airway contraction, and utilize drugs/strategies developed in Aim 2 to render OGR1 pro-relaxant as opposed pro- contractile. Collectively, these studies will help identify a novel signaling pathway in ASM that participates in the pathobiology of numerous airways diseases, and determine a means to target it therapeutically.
|Aisenberg, William H; Huang, Jessie; Zhu, Wanqu et al. (2016) Defining an olfactory receptor function in airway smooth muscle cells. Sci Rep 6:38231|
|Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) Î²-arrestin-biased signaling through the Î²2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16|
|Carr 3rd, Richard; Koziol-White, Cynthia; Zhang, Jie et al. (2016) Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms. Mol Pharmacol 89:94-104|
|Ghosh, Arnab; Koziol-White, Cynthia J; Asosingh, Kewal et al. (2016) Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Proc Natl Acad Sci U S A 113:E2355-62|
|Xie, Yan; Jiang, Haihong; Zhang, Qian et al. (2016) Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis. Respir Res 17:103|
|Pera, Tonio; Penn, Raymond B (2016) Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones. Pharmacol Ther 164:82-96|
|Dileepan, Mythili; Sarver, Anne E; Rao, Savita P et al. (2016) MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells. PLoS One 11:e0150842|
|Kim, Donghwa; Pauer, Susan H; Yong, Hwan M et al. (2016) Î²2-Adrenergic Receptors Chaperone Trapped Bitter Taste Receptor 14 to the Cell Surface as a Heterodimer and Exert Unidirectional Desensitization of Taste Receptor Function. J Biol Chem 291:17616-28|
|An, Steven S; Mitzner, Wayne; Tang, Wan-Yee et al. (2016) An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma. J Allergy Clin Immunol 138:294-297.e4|
|Billington, Charlotte K; Penn, Raymond B; Hall, Ian P (2016) Î²2 Agonists. Handb Exp Pharmacol :|
Showing the most recent 10 out of 38 publications