Role of DNA damage in Pulmonary Artery Hypertension

Pulmonary Arterial Hypertension (PAH) is a lethal disease of the pulmonary vasculature characterized by progressive remodeling of distal pulmonary arteries. If untreated, the median survival of patients with PAH is 2.8 years. A recent study found a higher prevalence of smokers among male patients compared to healthy controls, and a higher exposure to environmental tobacco smoke among women patients, suggesting that both active and environmental tobacco smoke exposure are risk factors of PAH. In this application, we will study the link between tobacco smoke and PAH. We hypothesize that PAH is triggered by a combination of two hits: (i) a “genotoxic” (genome-damaging) effect caused by tobacco smoke exposure and (ii) a “genetic” effect due to mutations in a PAH-linked gene,  BMPR2, which disrupt DNA repair, leading to accumulation of DNA damage and genome instability. Upon successful execution of this project, we will be able to elucidate how tobacco smoke synergizes with the genetic background of some individuals to trigger PAH. We will also provide novel drug targets for anti-PAH therapy.