Extracellular polycation signalling in alveolar and systemic inflammation

Critically ill patients often develop reduced immune function and inappropriate "leak" of fluid into the airspaces of their lungs, contributing to the high mortality rates. Evidence suggests that activation of a calcium-sensing receptor (CaSR) in their lungs may drive these unwanted processes, but this has not been studied comprehensively. To address this, I shall: - obtain immune cells from critically ill patients and establish if their function can be restored by suppressing CaSR; - grow the key lung cells, and assess whether their anti-leak and anti-infection functions are altered by targeting CaSR; - genetically remove CaSR from the key immune cells (called neutrophils) in mice, to work out how important neutrophil CaSR is in fighting lung infections. The proposal will define the importance of CaSR in critical illness, potentially suggesting new treatment approaches for severe infection, and provide me with knowledge I need to become a leader in this area.