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.
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.
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