In the previous cycle we characterized the ability of certain benzodiazepines, in cooperation with decreased extracellular pH, to regulate airway smooth muscle (ASM) signaling and function via activation of the proton- sensing G protein-coupled receptor (GPCR) OGR1 (Ovarian cancer G-protein coupled receptor 1 aka GPR68). Importantly, we discovered that the multiple signaling pathways activated downstream of OGR1 could be selectively activated (i.e., biased) to produce differential effects on ASM contraction and proliferation. In this second cycle we propose to: 1) delineate the mechanisms by which the biasing of OGR1 signaling occurs; 2) detail an additional, mitochondrial-dependent effector arm of benzodiazepines that also inhibits ASM contraction; and 3) employ modeling to develop more efficacious benzodiazepine-like drugs that target these mechanisms. These goals will be achieved through 3 Specific Aims.
In Aim 1 we will employ cell-based and integrative models of ASM contraction to clarify the how different benzodiazepines promote specific OGR1- and peripheral benzodiazepine receptor- signaling to regulate ASM contraction.
In Aim 2 will establish the mechanistic basis of biased OGR1 signaling by assessing structure-function properties of OGR1 that dictate G protein coupling, and the biasing function of arrestins.
In Aim 3 in collaboration with Core A we will employ molecular modeling to design new allosteric modulators to bias OGR1 signaling towards Gs/cAMP/PKA pathway activation and the associated therapeutic benefits, using the signaling and functional assays employed in Aims 1 and 2 to guide development and identify the most efficacious drugs. By establishing mechanisms mediating qualitative signaling by OGR1 and developing new agents that optimally bias OGR1 and promote bronchodilation, we will significantly advance the fields of both receptor biology and asthma therapeutics.
We have discovered that certain benzodiazepines have the ability to function as bronchodilators by acting on two poorly understood proteins expressed in airway smooth muscle: the cell surface receptor termed OGR1 and the mitochondria-associated proton termed the peripheral benzodiazepine receptor. We propose studies to better understand how these proteins function to relax airway smooth muscle and thereby inhibit the airway closure that occurs in patients with asthma. We will also take advantage of the unique resources provided by the Program Project grant to develop new, better benzodiazepine-like drugs to improve the likelihood of realizing these drugs as approved asthma therapeutics.
| Chaturvedi, Madhu; Schilling, Justin; Beautrait, Alexandre et al. (2018) Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors. Trends Biochem Sci 43:533-546 |
| Tliba, Omar; Panettieri Jr, Reynold A (2018) Paucigranulocytic asthma: Uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol : |
| Pera, Tonio; Deshpande, Deepak A; Ippolito, Michael et al. (2018) Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB J 32:862-874 |
| Ojiaku, Christie A; Cao, Gaoyuan; Zhu, Wanqu et al. (2018) TGF-?1 Evokes Human Airway Smooth Muscle Cell Shortening and Hyperresponsiveness via Smad3. Am J Respir Cell Mol Biol 58:575-584 |
| Kennedy, Joshua L; Koziol-White, Cynthia J; Jeffus, Susanne et al. (2018) Effects of rhinovirus 39 infection on airway hyperresponsiveness to carbachol in human airways precision cut lung slices. J Allergy Clin Immunol 141:1887-1890.e1 |
| Komolov, Konstantin E; Benovic, Jeffrey L (2018) G protein-coupled receptor kinases: Past, present and future. Cell Signal 41:17-24 |
| Lapadula, Dominic; Farias, Eduardo; Randolph, Clinita E et al. (2018) Effects of Oncogenic G?q and G?11 Inhibition by FR900359 in Uveal Melanoma. Mol Cancer Res : |
| Lotvall, Jan; Panettieri Jr, Reynold A (2018) Thank you and farewell after 15 years editing respiratory research. Respir Res 19:232 |
| Panettieri, Reynold A; Pera, Tonio; Liggett, Stephen B et al. (2018) Pepducins as a potential treatment strategy for asthma and COPD. Curr Opin Pharmacol 40:120-125 |
| Lo, Dennis; Kennedy, Joshua L; Kurten, Richard C et al. (2018) Modulation of airway hyperresponsiveness by rhinovirus exposure. Respir Res 19:208 |
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