Thoracic aortic aneurysm and dissection cause significant morbidity and mortality, but the underlying molecular mechanisms remain largely elusive. We generated a zebrafish model for aortic dissection, quadruple knockout for smad3a;smad3b;smad6a;smad6b. Multi-omic analysis identified upregulation of pigmentation pathways as a target for therapeutic compounds. In a second aim, we are developing more efficient protocols to generate knockin zebrafish models.