Wednesday, April 24, 2024
4/24/2024
PROJECT ABSTRACT Asthma is a chronic inflammatory disease of the lungs that is characterized by airway obstruction and bronchospasm. While there are many factors that contribute to development of asthma and other inflammatory airway diseases, the generation of reactive oxygen species (ROS) within the airway can lead to exasperation of airway inflammation and contributes greatly to pathophysiology of airway disorders like asthma. The gold- standard for treatment of asthma and other bronchoconstrictive disorders is inhalation of ß2-adrenergic receptor (ß2AR) agonists, which quickly relax the airway tissues and reduce bronchospasms, allowing for greater pulmonary function. Recently, our laboratory has demonstrated that agonism of ß2AR leads to robust formation of ROS. However, our work also shows that ROS are required for ß2AR function, as inhibition of ROS abrogates all ß2AR signaling. These results suggest that some level of ROS are required for stabilization of functional ß2AR, and indeed, we show in airway epithelial cells that ROS regulate the ß2AR by directly oxidizing it. Importantly, the oxidation of ß2AR is decreased in tissue from mice that lack appropriate ROS- generating enzymes, and also regulates the receptors function in human airway cells, suggesting that ROS interplay may be important for homeostatic pulmonary function of ß2AR. The overall goal of this project is to examine the ROS generation and ROS-mediated oxidation of ß2AR in normal and asthma-diseased airways. In this regard, we plan to: 1) Localize the exact site(s) of the ß2-receptor that are oxidized by ROS, and assess the functional consequences of this oxidation in normal and asthma-diseased cells. 2) Characterize the signaling pathways that facilitate both ROS generation and ß2-recptor oxidation in normal and asthma- diseased cells. Results of this work will shed light on the role of ROS as regulators of GPCR function, and establish a knowledge base towards understanding the ROS-ß2-receptor linkage in mammalian airway cells that modulate the clinical response to ß2AR-agonist treatment. This work will also reveal if there are differences in the ß2AR-ROS axis in asthma diseased airways.
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