Hemodynamic regulation of valve and great vessel morphogenesis

Only about 10% of human CHD cases have an identifiable genetic cause. Causal interpretations of genetic deletions (even lineage restricted) are confounded by variable penetrance and genetic compensation as development progresses. We utilize our innovative local hemodynamic gain/loss experimental and computational strategies to directly elucidate the molecular, cellular, and morphogenic adaptations that are orchestrated by hemodynamic forces, both to promote normal and malformed outflow valves and great vessels. We can create focal ablations or obstructions within the beating embryonic heart, the proximal/distal outflow tract, and the pharyngeal arch artery network (which collectively form the dual outflow valves and great vessels) in live avian embryos using our innovative femtosecond laser ablation technology. We directly quantify the early and late in vivo consequences of these focal lesions using high frequency ultrasound, in vivo micro-CT, and CFD simulations. We determine how these hemodynamic perturbations affect local cell lineage migrations (via established quail-chick chimeras and/or local electroporation based labeling and genetic modification, cell phenotypes and matrix composition. Armed with this fundamental knowledge, we explore how in vivo ablation of hyperplastic cushions and/or local tissue obstructions, or directed hemodynamic redistribution through local vascular occlusion of can counteract genetic mutations in cardiac and great vessel morphogenesis.