Identification de nouvelles cibles thérapeutiques pour corriger le remodelage vasculaire associé à l'hypertension artérielle pulmonaire

 

Olivier Boucherat

Institut universitaire de cardiologie et de pneumologie de Québec

 

Domaine : santé circulatoire et respiratoire

Programme Chercheurs-boursiers - Junior 1

Concours 2018-2019

Pulmonary arterial hypertension (PAH) is characterized by the obstruction of the lumen of lung blood vessels, putting an excessive strain to the right chambers of the heart, leading to heart failure. 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. Therefore, the identification of new therapeutic targets is a pressing need.

Others and I have shown that PAH is due to an excessive multiplication and resistance to death of the cells composing lung blood vessels. Surprisingly, this exaggerated cell survival and proliferation occur despite the fact that PAH patient lungs and blood vessels are exposed to tremendous amount of environmental stress, which in a healthy person will results in the elimination of the cells rather to their survival. Therefore, I hypothesize that PAH cells have developed mechanisms to minimize or overcome damage imposed by adverse environmental conditions and enabling their survival and multiplication and subsequent obstruction of the lumen. I believe that the identification and characterization of these mechanisms constitute vulnerabilities that can be therapeutically exploited.

Using tissues and cells from healthy and PAH patients, animal models of the diseases, genetically modified mice and molecular and pharmacological tools, I will demonstrate that 1) several factors are increased or reorganized spatially within the cell to counteract the deleterious effect of stress that jeopardize their survival, and that 2) their specific inhibition improves PAH in animal models. In identifying new factors critically involved in PAH development and validate therapeutic tools, accomplishment of my program would therefore represent a major breakthrough in the understanding of PAH and pave the way for novel treatment strategies with potential applicability to several cardiopulmonary disorders affecting both children and adults and characterized by similar abnormalities.