KCNRG in the pulmonary circulation

Pulmonary arterial hypertension (PAH) is a form of a broader condition known as pulmonary hypertension, which is increased blood pressure in the lungs. At PAH, this increased pressure in the vessels is caused by obstruction in the small arteries in the lungs. As a result, the right heart has to work harder to pump the blood through the lungs. The extra effort eventually causes the heart muscle to become weak and fail. Symptoms of PAH include shortness of breath (dyspnoea), especially with exertion, chest pain and fainting spells. PAH is a chronic, progressive disease that severely limits patients` exercise capacity and life expectancy. The progressive nature of this disease also means that an individual may have only mild symptoms at first, but eventually require treatment and medical care to maintain a reasonable quality of life. The exact cause of PAH is still unknown, and although the disease is treatable, there is no cure. PAH usually affects women between the ages of 30and 60. Individuals with PAH may go undiagnosed for years because their symptoms are either mild or non- specific, or only occur during strenuous exercise. The remodelling of the pulmonary vessel is still not fully understood. It is characterised not only by an accumulation of various vascular cells in the pulmonary artery wall (smooth muscle cells, endothelial cells, fibroblasts, myofibroblasts and pericytes), but also by excessive infiltration of inflammatory cells. Disturbed metabolism, inflammation and dysregulation of growth factors can lead to this proliferative state. Pathobiology and pharmacology strongly support ion channels as essential players in the disease development. Dysfunctional ion channels may lead to calcium overload, vasoconstriction and proliferation. In our idiopathic PAH cohort, we detected upregulation of a new gene which might cause dysfunction of ion channels. We will address our questions using our large bank of human lung tissue and cells and a broad combination of state-of-the-art techniques in cell physiology, molecular biology, physiology and proteomics together with our collaborative partner. Our proposed experiments and the corresponding Hungarian project are closely linked and build on each other. Innovation: Our proposal could represent a new molecular mechanism of PAH and offer a new therapeutic target to fight the disease. The collaboration will benefit greatly from our expertise in pulmonary hypertension, the large human lung tissue bank and the existing techniques to study the physiological consequences of ion channel function changes in vivo at the Medical University of Graz, supported by the long experience in electrophysiology and ion channel manipulation at Semmelweis University Budapest. The new proposal aims to strengthen this interaction to achieve maximum synergy and added value in terms of research results.