Asthma is a complex disease that results in airway smooth muscle (ASM) contraction and subsequent airway constriction. The major drugs used to treat asthma include B-agonists that promote ASM relaxation, Gq-coupled receptor antagonists that inhibit bronchoconstriction, and corticosteroids that reduce inflammation. Recent studies suggest that long acting p-agonists (LABAs) increase the risk of having a severe asthmatic attack that can result in death. While the mechanism whereby B-agonists cause such severe side effects clearly needs to be defined, B2-adrenergic receptor (B2AR) desensitization and B-arrestin- mediated signaling appear to contribute to this process. We hypothesize that biased agonists that selectively promote B2AR interaction with Gs will serve as an effective way of treating asthma.
In aim 1, we propose to test this hypothesis by analyzing the ability of lipidated B2AR peptides (pepducins) that we have identified to promote Gs-biased coupling of the B2AR in human ASM cells and precision cut lung slices. Another approach to attenuate GRK/B-arrestin-mediated regulation of P2AR function is to selectively inhibit these proteins.
In aim 2, we will better define the GRKs and B-arrestins that regulate B2AR function in human ASM cells and then use inhibitory peptides, small molecules and screening approaches to target these pathways. Inhibition of Gq signaling can also serve as an effective means of treating asthma, although there are many Gq-coupled receptors that are activated in asthma. We hypothesize that inhibiting a single receptor is an ineffective way of attenuating ASM contraction and, in aim 3, propose to develop broad-based inhibitors of Gq signaling. These include a pepducin that functions as a broad-based antagonist of Gq signaling, lipidated Gaq peptides that selectively disrupt GPCR/Gq coupling, and small molecule inhibitors of GBy-mediated signaling. Overall, these studies should: 1) identify pepducins that have substantially preferred properties over the p-agonists that are currently used to treat asthma;2) identify GRK/p-arrestin pathway inhibitors that enhance P2AR signaling;and 3) identify compounds that can effectively inhibit airway smooth muscle contraction.

Public Health Relevance

Asthma is a complex disease that affects -8% of the US population and is manifested by enhanced airway inflammation that leads to airway smooth muscle contraction and subsequent airway constriction. The proposed research will utilize several strategies to develop ways of enhancing airway smooth muscle relaxation and inhibiting airway smooth muscle contraction. These efforts should lead to a better understanding of the mechanisms involved in asthma and may lead to the development of better drugs for the treatment of airway diseases such as asthma.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
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) β-arrestin-biased signaling through the β2-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) β2-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) β2 Agonists. Handb Exp Pharmacol :

Showing the most recent 10 out of 38 publications