Thomas Brett, PhD

Calcium-activated chloride channels (CaCCs) play a central role in airway health and disease. In homeostasis, they contribute to normal mucus salinity and hydration. However, overactivation of CaCCs in the airway has been linked to mucus cell metaplasia (MCM), and consequent excess mucus production in chronic airway diseases. The secreted protein CLCA1 is a potent modulator of CaCCs and its overexpression drives MCM through an unknown mechanism. Although CLCA1 has long been linked to asthma and COPD, and considered as a drug target for the treatment of these diseases, progress in this area has been limited due to the lack of mechanistic insight into CLCA1 function. Understanding of the structural mechanism by which CLCA1 modulates CaCCs could lead to the design of inhibitors that serve as anti-mucus therapeutics. In this pilot project, we focus on elucidating the structural and biochemical basis by which CLCA1 modulates CaCCs.