Thoracic aortic aneurysm (TAA) is an abnormal widening of the aorta in the chest, caused by the weakening of the aortic wall. TAAs can lead to rupture or dissection, a devastating complication with a mortality rate of 50%. Despite considerable efforts to gain insights on the molecular mechanisms underlying TAAs, there is currently no therapy that effectively stops or reverses TAA development. Single-cell RNA sequencing (scRNA-seq) is emerging as a ground-breaking technology to investigate gene expression at single-cell level and is opening new avenues to discover yet unexplored disease pathways. In my project, I will apply this technique to investigate a novel TAA disorder caused by bi-allelic pathogenic variants in the IPO8 gene, recently discovered in our Cardiogenomics research group. I will search for differentially expressed genes (DEGs) within the different aortic cell populations from an Ipo8-/- mouse model that recapitulates the human aortic aneurysmal phenotype. I will also investigate shared DEGs between Ipo8-/- mice and additional TAAs mouse models to find convergent disease pathways in clinically related TAA disorders. Subsequently, I will validate the role of the identified candidate culprits in mouse TAA development in a human setting, by using CRISPR-inhibition or -activation in iPSCs derived vascular smooth muscle cells or endothelial cells. The predicted outcomes will potentially pinpoint novel TAA drivers and hence, unveil potential new therapeutic targets.