Contraction and proliferation are two important functions of airway smooth muscle (ASM), and dysregulation of these functions is believed to be important in the pathogenesis of asthma. G protein-coupled receptors (GPCRs) are known to be important regulators of ASM function, capable of either promoting (Gq-coupled GPCRs) or inhibiting (Gs-coupled GPCRs) ASM contraction and proliferation. We propose to characterize how these competing classes of GPCRs desensitize when exposed to their cognate agonists, and determine whether specific inhibition of desensitization of the Gs-coupled receptor (2-adrenergic receptor can render the most common asthma therapy, beta-agonist, a more effective antagonist of ASM contraction and proliferation. We will employ state of the art biochemical, molecular, and genetic approaches to characterize the specificity of various mutant inhibitory constructs of GPCR kinases (GRKs) for both Gq- and Gs- coupled GPCRs, and establish the effectiveness of these constructs in regulating receptor signaling and associated functional consequences.
Aims 1 and 2 will use both human and murine ASM cell cultures to determine the effect of GRK regulatory domain peptides or mutants, and siRNA-mediated GRK knockdown, on cellular signaling events important to ASM contraction and proliferation.
Aim 3 will determine the functional consequences of this regulation by assessing changes in ASM contraction (both in vivo and ex vivo) and proliferation. The proposed studies will identify for the first time how desensitization mechanisms preferentially influence competitive GPCR signaling events in ASM and link this regulation to functional outcomes. Results from these studies will establish the potential usefulness of targeting GRK-mediated desensitization mechanisms as a therapy for obstructive airway diseases: Relevance to Public Health: The proposed studies will test whether the (2-adrenergic receptor is the receptor in airway smooth muscle most prone to desensitization mechanisms that cause a loss of responsiveness, and examine whether a novel strategy to selectively block this desensitization could improve the beneficial effects of (-agonist therapy for asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL058506-16
Application #
8713373
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (02))
Program Officer
Banks-Schlegel, Susan P
Project Start
1997-08-01
Project End
2018-01-31
Budget Start
2013-09-01
Budget End
2014-01-31
Support Year
16
Fiscal Year
2013
Total Cost
$387,849
Indirect Cost
$137,624
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Penn, Raymond B (2014) Far from ""disappointing"". Am J Respir Crit Care Med 189:360

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