The role of airway epithelial CRAC channels in allergic lung inflammation

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Abstract: For many years, the primary responsibility of airway epithelial cells was considered to be the maintenance of barrier function. Recently, airway epithelial cells (AECs) have emerged as key orchestrators of immune responses. For instance, AECs can respond to allergen presence in the airway lumen and thereby direct immune cells, promoting allergic sensitization. The allergens can activate pattern recognition receptors on AECs leading to the production of immunostimulatory lipids and proteins. Many of these receptors transduce signals through the ubiquitous signaling ion Ca2+. Another class of molecules that can activate receptors on AECs is damage-associated molecular patterns (DAMPs). One DAMP that has been linked to Ca2+ signaling and asthma is ATP. Extracellular ATP is known to contribute both to allergic sensitization and chronic inflammation. These effects are likely linked to ATP-mediated production of cytokines, prostaglandins and mucin proteins from AECs. We recently discovered Calcium Release-Activated Calcium (CRAC) channels are a major mechanism for Ca2+ signaling in AECs ultimately driving cytokine production. Preliminary data suggests that ATP receptors can activate CRAC channels in AECs. However, how CRAC channels interface with ATP signaling to drive inflammatory processes is unclear. Therefore, in this proposal, we will further interrogate the significance of AEC CRAC channels in airway inflammation and disease models of asthma. We will do this through the following aims. Aim 1: Determine the mechanism for how AEC CRAC channel activation induces prostaglandin E2 synthesis. Aim 2: Investigate the role of AEC CRAC channels in receptor-stimulated exocytosis. Aim 3: Define the role of AEC CRAC channels in allergic lung inflammation in vivo. We will approach these studies through the use of an integrated analysis using calcium imaging, molecular biology, ELISAs, live cell imaging, tissue-specific knockout mice, histology and assessment of lung function. This research will occur under the direct mentorship of Dr. Murali Prakriya. Collectively, this research has the potential to unveil new targets to inhibit the chronic inflammation driving asthma.