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.
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