Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a progressive and ultimately fatal disease with a median survival from diagnosis of approximately six years despite modern treatments. Up to 1 in 20,000 people are affected, and no available therapies cure or prevent this disease. PAH is characterized by pulmonary arterial endothelial cell (PAEC) and smooth muscle cell (PASMC) dysfunction leading to increased pulmonary vascular resistance and death from right heart failure. Abnormal hemodynamic forces are the primary cause of PAH in some patients, and in all cases may contribute to progression. The small pulmonary arteries in PAH are exposed to both increases in shear stress and pressure forces. Increased shear stress has previously been shown to cause EC changes mimicking those seen in PAH. Dr. Rayner has obtained preliminary data showing that PAECs from subjects with PAH have divergent transcriptomic responses to pathologically high shear stress when compared with controls. This suggests that patient abnormalities in shear-sensitive pathways may be a potential unifying mechanism in PAH that could provide targets for future therapeutics. Dr. Rayner’s overall goal is to define how shear and pressure forces combine with underlying patient factors to drive vascular dysfunction and promote PAH. Dr. Rayner has a research program focused on applying novel bioengineering techniques to the study of PAH. His research proposal will use a resistor-coupled microfluidic device to allow pressure and shear forces to be evaluated both individually and in combination. Dr. Rayner has also developed a novel pulmonary arteriole-on-a-chip (AOC) model that will be employed in this proposal to evaluate EC-SMC signaling and coordinated vascular behavior. Dr. Rayner’s research goal will be accomplished through three aims: 1) Evaluate the effects of shear and pressure on control and PAH PAECs in a resistor-coupled microfluidic platform; 2) Determine how pressure and patient factors influence cell phenotypes in PASMC-only AOCs; 3) Identify the effect of hemodynamic and patient factors on cell phenotypes and PAEC to PASMC signaling within patient-specific multicellular AOC models. These specific aims are well-aligned to the main training aims of Dr. Rayner’s Career Development Plan, which are to gain essential additional training in pulmonary vascular cell biology, bioinformatics, and vascular engineering. Dr. Rayner will gain these skills through a combination of formal didactics, experiential training, and close mentorship by a world-class team of scientists with relevant expertise. These new skills will augment his background in bioengineering and translational PAH research and facilitate his overall goal of developing into an independent physician-scientist doing basic and translational research on PAH. With his own unique engineered vascular platforms and the data generated through this research, Dr. Rayner will be well-positioned to submit a competitiv...