Grant: Project Grant

Patients with pulmonary arterial hypertension have a dysfunction of the cells constituting the wall of their arteries in the lungs. Like cancer cells, PAH cells are characterized by exaggerated capacity to multiply and resistance to death resulting in a progressive narrowing or obstruction of the vessels. Indeed, if the blood vessels tighten up, making the space for the passage of blood narrower, it takes greater pressure to get the same amount of blood through to its destination. The heart has to work harder to pump blood through those arteries. The heart progressively fails causing shortness of breath and poor exercise capacity, which rapidly culminate in death. In spite of recent progress in our understanding of the mechanisms involved in this disease, no substantial modification of the rapid progression and fatal course of this disease has been achieved, leaving lung transplantation as the only treatment in endstage PAH. Therefore, the identification of new therapeutic targets is a pressing need. In the present proposal, we hypothesize that overactivation of a factor called eIF5A contributes to the obstruction of the vessels in PAH by stimulating the expression of a set of genes involved in cell survival and proliferation. To test the validity of our hypothesis, we will 1) determine whether activated eIF5A contributes to PAH cells' anomalies; 2) assess whether inhibition of its activation improves PAH in animal models and 3) identify the genes whose expression is dependent on activated eIF5A.