P10 - Role of TRP channels for pulmonary ion homeostasis and alveolar bioenergetics
Defects in pulmonary ion homeostasis, whether acquired or inherited, can result in diseases such as cystic fibrosis, oedema, and compromised respiratory protection against pollutants and pathogens. However, the molecular identity of transport proteins responsible for ion homeostasis in the lung remains poorly understood. We have previously shown that the channel-kinase TRPM7 functions as a prime route for the cellular entry of divalent cations, especially Mg2+. Apart from the homeostatic control of cellular Mg2+ levels, TRPM7 regulates multiple Zn2+- and Ca2+-dependent signalling pathways. Moreover, TRPM7 may act as the prime mechanism for the uptake of toxic trace metals, including Cd2+, Ni2+, and Mn2+. Our studies have shown that both TRPM6 and TRPM7 are highly expressed in epithelial alveolar type II (ATII) cells and bronchial epithelial cells, suggesting their essential role in maintaining cation influx in these cells. Interestingly, knocking out Trpm6 in mice has been linked to impaired pulmonary surfactant secretion and the development of lung emphysema, a hallmark of chronic obstructive pulmonary disease (COPD). To this end, our project aims to uncover the role of TRPM6 and TRPM7 in the metabolic activity of primary ATII cells and their responses to toxic factors such as trace metals and ROS. We will also explore the effectiveness of newly discovered pharmacological modulators of TRPM6 and TRPM7 in protecting ATII cells from harmful agents using our collection of cell models and gene-modified mice.