Thoracic aortic aneurysms and dissections (TAA/D) are life-threatening conditions that often occur in younger individuals without traditional cardiovascular risk factors, suggesting a strong genetic component. However, over 80% of TAA/D cases lack identified mutations, and more than 87% of dissections occur below current surgical thresholds, underscoring the need for better mechanistic understanding of TAA/D pathogenesis. In response to stress, SMCs in the aorta undergo “fate switching”, adopting a “synthetic” state marked by increased proliferation, migration, and extracellular matrix remodeling. Synthetic switching is consistently elevated in TAA/D patient samples, suggesting a potential pathogenic role.

I recently identified the transcriptional regulator PRDM16 as a specific repressor of synthetic SMC switching in atherosclerosis. For Objective 1, I aim to test whether PRDM16 similarly modulates SMC behavior in TAA/D and if its sustained expression can prevent TAA/D. In objective 2 I take an unbiased approach, creating a single-cell RNAseq atlas of human TAA/D using a novel method, to identify divergent SMC states between control, dilated and dissected aortae. Resulting targets will be validated in vitro. With my research I aim to advance our understanding of how SMC fate changes contribute to TAA/D, to support better patient risk stratification in the future.