Many major signaling events in the lung are carried out by the superfamily of G-protein coupled receptors (GPCRs). These include bronchial smooth muscle relaxation and contraction, mucous secretion, ciliary beat frequency, inflammation, immune cell trafficking, pulmonary vascular tone and permeability, and alveolar fluid and electrolyte transport, as well as many yet to be defined functions. Approximately 75 GPCRs are estimated to be expressed in human lung. Within the next five years, the great majority of all therapeutic agents will target GPCRs. However, the physiologic, pathologic, and pharmacologic behavior of GPCR signaling displays substantial interindividual variability which is thought to be due to common variants (polymorphisms) of the genes encoding these receptors. Such polymorphisms have been estimated to account for as much as 50% of the variability in the response to therapeutic agonists and antagonists targeted to GPCRs. Indeed, with just one GPCR, the (2-adrenergic receptor, we have shown that coding and promoter polymorphisms alter receptor expression, function, and regulation in vitro in cells, and in asthmatic patients, they are associated with clinical phenotypes and the response to beta-agonist therapy. The long-term goals of this proposal are to identify polymorphisms of up to 20 pulmonary GPCR genes, and by the use of recombinant expression techniques to delineate their biochemical and pharmacologic impact on cellular signaling relevant to lung homeostasis and pathobiology.
In Aim 1, the polymorphisms of these 20 GPCR genes will be delineated in the promoter, 5' untranslated, coding, intron/exon junctions, and 3' untranslated regions from genomic DNA samples from a cohort of 60 ethnically diverse individuals.
In Aim 2, the common combinations of polymorphisms (haplotypes) will be delineated in the population.
In Aim 3, constructs will be developed and model cell systems utilized for recombinant expression of GPCR haplotypes to determine the biological effects of polymorphisms on receptor expression, signaling, or regulation. These studies will provide the basis for interindividual susceptibility and therapeutic responsiveness, the variability in pathobiology, and the potential for developing new treatment strategies, for a diverse range of lung diseases including asthma, pulmonary hypertension, pneumonia, pulmonary fibrosis, COPD, and pulmonary edema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071609-05
Application #
7269406
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Banks-Schlegel, Susan P
Project Start
2003-09-01
Project End
2009-07-31
Budget Start
2007-09-01
Budget End
2009-07-31
Support Year
5
Fiscal Year
2007
Total Cost
$352,012
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Wang, Wayne C H; Pauer, Susan H; Smith, Dan'elle C et al. (2014) Targeted transgenesis identifies G?s as the bottleneck in ?2-adrenergic receptor cell signaling and physiological function in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 307:L775-80
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
Liggett, Stephen B (2013) Bitter taste receptors on airway smooth muscle as targets for novel bronchodilators. Expert Opin Ther Targets 17:721-31
An, Steven S; Wang, Wayne C H; Koziol-White, Cynthia J et al. (2012) TAS2R activation promotes airway smooth muscle relaxation despite ?(2)-adrenergic receptor tachyphylaxis. Am J Physiol Lung Cell Mol Physiol 303:L304-11
Clark, Adam A; Liggett, Stephen B; Munger, Steven D (2012) Extraoral bitter taste receptors as mediators of off-target drug effects. FASEB J 26:4827-31
Trian, Thomas; Burgess, Janette K; Niimi, Kyoko et al. (2011) ?2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D. PLoS One 6:e20000
Wang, Wayne C H; Juan, Aster H; Panebra, Alfredo et al. (2011) MicroRNA let-7 establishes expression of beta2-adrenergic receptors and dynamically down-regulates agonist-promoted down-regulation. Proc Natl Acad Sci U S A 108:6246-51
Johnson, J A; Liggett, S B (2011) Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin Pharmacol Ther 89:366-78
Deshpande, Deepak A; Robinett, Kathryn S; Wang, Wayne C H et al. (2011) Bronchodilator activity of bitter tastants in human tissue. Nat Med 17:776-8
Robinett, Kathryn S; Deshpande, Deepak A; Malone, Molly M et al. (2011) Agonist-promoted homologous desensitization of human airway smooth muscle bitter taste receptors. Am J Respir Cell Mol Biol 45:1069-74

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