New grant (NIH): Blood Flow Regulation of Pharyngeal Arch Artery Morphogenesis
Jonathan Butcher was awarded a grant through the National Science Foundation entitled, “Blood Flow Regulation of Pharyngeal Arch Artery Morphogenesis.”
Early embryonic heart outflow is delivered via symmetric pairs of vessels called the pharyngeal arch arteries (PAA). This vascular manifold remodels into portions of the pulmonary arteries, aorta, and other critical great vessels. Elucidation of the Microenvironmental control of PAA remodeling is a key basic science need with broad potential for downstream engineering and regenerative applications.
Despite substantial effort searching for genetic regulation and thereby causes of great vessel malformations, mutations explain only a small minority of defects, with substantial phenotype variability and poor penetrance. This proposal is significant because it creates and applies new technology to uniquely target a critical but underexplored alternative hypothesis: that microenvironmental signals orchestrate the proper remodeling of the PAA network. The non-invasive localized occlusion/ablation strategies developed herein can transform the study of cardiovascular developmental biology. The novel automated quantitative 3D multi-data mapping strategy proposed will accelerate mechanism discovery with reduced variability. Integration of computational fluid dynamics (CFD) analysis with multi-scale 3D-0D lumped parameter modeling enables prediction of downstream adaptations of the vascular network. By analyzing actual anatomy from multiple embryos rather than using a single "consensus" geometry, we will contribute key lacking information regarding the variability of morphogenic outcomes to local deviations in cellular composition and/or flow fields, and further their tolerance to acute changes in hemodynamic signaling.