Mechanotransduction of Shear Stress and Genetic Response in the Embryonic Heart

该奖项的研究目标是利用互补的生物力学和遗传方法来研究生物力学应力如何影响胚胎心脏。当液体和血细胞在形成的胚胎心脏中移动时，它们对心内膜和血管内皮壁施加剪切和正常的压力。这些压力为发育中的心脏提供了感知到的机械“反馈”。过多或过少的压力都会产生病理影响，在出生前后严重扰乱心脏结构和功能。根据该奖项进行的研究将应用一种新的定量成像方法来研究胚胎心脏中正常和病理生物力学力对活斑马鱼胚胎心脏形态和功能的影响。与此同时，基因实验将通过定义由kruppel -like factor - 2 （KLF2）转录因子（一种已知的应激反应基因）调控的基因队列，研究改变的生物力学力是如何转化为遗传反应的。如果成功，这些研究将有助于确定表观遗传生物力学因素如何以及何时调节脊椎动物心脏的早期形态发生。确定KLF2基因网络将有助于了解哪些特定的基因产物在胚胎心脏非遗传编码（生物力学）力量作用下发生改变。最终，这一知识将有助于改善先天性心脏病的子宫内诊断、治疗和干预措施。教育计划的重点是培养学生在心脏生物力学和遗传学的本科和研究生水平。新的定量成像工具和方法将适用于多种心脏突变体的研究。

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.