The research objective of this award is to use complementary biomechanical and genetic approaches to investigate how biomechanical stresses impact the embryonic heart. As fluid and blood cells move through the forming embryonic heart, they exert shear and normal stress upon the endocardial lining, and upon the blood vessel endothelial walls. These stresses provide mechanical 'feedback' sensed by the developing heart. Too much or too little stress can have pathological effects that critically perturb cardiac structure and function both before and after birth. Studies conducted under this award will apply a novel quantitative imaging methodology to investigate the effects of normal and pathological biomechanical forces in the embryonic heart on cardiac morphology and function in live zebrafish embryos. In parallel, genetic experiments will investigate how altered biomechanical forces translate into a genetic response by defining the cohort of genes regulated by the Kruppel-like-factor2 (KLF2) transcription factor, a known stress response gene.
If successful, these studies would help identify how and when epigenetic biomechanical factors regulate the early morphogenesis of the vertebrate heart. Identifying the KLF2 gene network will provide insight into which specific gene products are altered in response to non-genetically encoded (biomechanical) forces operating in the embryonic heart. Ultimately, this knowledge should lead to improved in-utero diagnostics, treatments and interventions for congenital heart disease. The educational plan focuses on training students in cardiac biomechanics and genetics at the undergraduate and graduate level. New quantitative imaging tools and methods will be applicable for study of multiple cardiac mutants.
