Grant: Operating Grant

Hypoxic pulmonary vasoconstriction is an important mechanism by which the lung redistributes blood flow from poorly ventilated to better aerated lung areas, thus improving gas exchange and oxygen uptake. This is achieved by rapid contraction of lung blood vessels in response to low oxygen levels. However, the cellular mechanisms underlying this important response are yet incompletely understood. Here, we propose that CFTR, the ion channel mutations in which cause the common genetic and frequently fatal disease cystic fibrosis, plays an important regulatory role in hypoxic pulmonary vasoconstriction. Importantly, this recognition may explain in part the progressive impairment in gas exchange in patients with cystic fibrosis. Notably, CFTR is not only an ion channel for chloride, but also plays a critical role in regulating the trafficking and signaling of sphingolipids, an important group of lipid molecules which serve as signaling messengers both inside and outside of the cell. We hypothesize that sphingolipids play an important role in hypoxic pulmonary vasoconstriction by changing the composition of lipid rafts, i.e. microdomains of the plasma membrane which serve as structural and functional clusters of receptors and signaling molecules, and that this effect requires CFTR. Using a combination of state-of-the-art analytical techniques in cultured cells, isolated organs and experimental animal models, we will put this hypothesis to the test. The results of this project are expected to profoundly expand our understanding of one of the basic regulatory mechanisms of lung function and gas exchange. The identification of impaired hypoxic pulmonary vasoconstriction as an important cause of compromised gas exchange in cystic fibrosis is expected to open new therapeutic strategies for the treatment of this disease.