Determining Novel SMURF1 Signalling Pathways and Precision Medicine Strategies in Patients with Pulmonary Arterial Hypertension (360G-Wellcome-206632_Z_17_Z)

Pulmonary arterial hypertension (PAH) is a rare, but devastating disease that leads to increased pulmonary vascular resistance, right heart failure and death. Despite clear clinical and biological differences between individual patients with PAH the treatment is uniform, based on an algorithm that matches the number of vasodilator drugs to functional class. I aim to establish SMURF1 inhibition as a novel anti-proliferative therapy and pathway for precision medicine for patients with PAH. I have demonstrated that SMAD-specific ubiquitin ligase regulatory factor-1 (SMURF1) is critical to pulmonary vascular remodelling and experimental PAH, and that SMURF1 mRNA expression is detectable and increased in peripheral blood from patients with PAH. In November 2015 my collaborators (Novartis) patented a series of SMURF1 inhibitors. Through this Fellowship I will use cutting edge RNA and protein profling techniques to determine mechanism though which SMURF1 mediates disease pathology and, using samples and clinical data from the worlds largest and best genotyped-phenotyped cohort of patients with PAH (the UK National Cohort), investigate means of identifying patients with cellular abnormalities related to SMURF1 who may benefit from a SMURF1 targeted therapy.