ATP13A3, een polyamine transporter betrokken bij pulmonale arteriële hypertensie en neuroblastoom

Pulmonary Arterial Hypertension (PAH) is a progressive and lifethreatening condition with a poor survival due to the lack of an adequate cure. This highlights an unmet need for new therapeutic strategies for PAH treatment. Recently, a genetic screen on a cohort of PAH patients revealed pathological and dominant mutations in an uncharacterised gene, ATP13A3. ATP13A3 is closely related to ATP13A2, and the host lab proved that ATP13A2 is a polyamine transporter. Polyamines are vital molecules for the cell and polyamine dysregulation is implicated in various diseases. Based on strong preliminary data, we hypothesize that ATP13A3 is also a polyamine transporter. Dominant PAH mutations may increase polyamine transport and uptake in cells, causing toxic accumulation of polyamines in the cell. To test this hypothesis and validate ATP13A3 as a drug target, we would like to (i) establish that ATP13A3 is a polyamine transporter, (ii) study the effect of PAH mutants on polyamine homeostasis; and (iii) elucidate the ATP13A3- dependent PAH disease mechanism in cellular models and determine if the disease-phenotype is reversed upon ATP13A3 inhibition. Towards a drug screening program to identify ATP13A3 inhibitors, we will optimize assays for high throughput screening with the Centre for Drug Design and Discovery. The role of ATP13A3 in more advanced PAH models will be explored in collaboration with Dr. N. Morrell at the University of Cambridge.