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 multiplicate 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 end-stage PAH. Therefore, the identification of new therapeutic targets is a pressing need. Although exposed to stressful conditions that jeopardize their survival, PAH cells continue to multiplicate indicating that these cells have developed adaptive protective response allowing them to survive. Nevertheless, the factors implicated in this pathological protective response remains largely unknown. In the present proposal, we hypothesize that a factor called CHK1 known to confer resistance to harmful stress conditions is overexpressed in PAH cells leading to the development of PAH. To test the validity of our hypothesis, we will 1) determine whether CHK1 is increased in PAH cells and contributes to PAH cells' anomalies; 2) decorticate the mechanisms by which CHK1 acts; and 3) assess whether inhibition of CHK1 improve PAH in animal models.