Collaborative Research: Deciphering the synergistic interaction between hemodynamics and genetics that form the heart

在早期心脏发育过程中，血流和遗传过程相互影响，以确保有效心脏的形成。然而，在心脏的形成和生长过程中，基因和血流究竟是如何相互作用的，这在很大程度上仍是未知的。加州大学欧文分校（UCI）和俄勒冈健康与科学大学（OHSU）之间的这项合作研究将使用先进的成像方法和计算模拟来揭示改变的血流量如何影响程序化的遗传过程，反过来，改变的遗传过程如何改变血流量，导致心脏缺陷。这个项目的结果将最终指导在婴儿出生前治疗心脏缺陷的方法。为了进一步扩大该项目对社会的影响，在加州和俄勒冈州的高中二年级，三年级和四年级的学生将参加外展活动，让学生参与科学活动，以了解心脏发展和培养团队科学技能。虽然血液流动和遗传过程都有助于心脏发育，但它们究竟如何相互作用和相互影响，以及血液流动和遗传在心脏畸形易感性中所起的协同作用尚不清楚。该项目的智力价值在于阐明了心脏发育过程中血液流动和遗传过程之间的相互联系。更具体地说，该项目将利用两种互补的鸟类心脏发育模型，研究基因表达对血流量改变的早期变化，以及血流量对信号改变的早期变化。该项目将集中在三个主要目标上：(1)通过先进的工程方法确定正常和异常心脏形成过程中的血流和血流诱导的应激；(2)通过生成心脏适应的时空图，识别和量化细胞对正常和受干扰心脏发育的反应；(3)通过DNA甲基化和RNA测序确定心脏组织中由于早期扰动而产生的遗传和表观遗传适应。作为更广泛的影响，该项目的结果将最终指导胚胎心脏发育的基础知识，帮助制定策略，以提高心脏缺陷的诊断，预防心脏畸形，并最终指导早期胎儿干预，以改善心脏缺陷的不良影响。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

During early cardiac development, blood flow and genetic processes influence each other to ensure formation of an efficient heart. However, how exactly genes and blood flow interact with one another during formation and growth of the heart remains largely unknown. This collaborative research between the University of California at Irvine (UCI) and the Oregon Health & Science University (OHSU) will use advanced imaging methods together with computational simulations to unravel how altered blood flow affects programmed genetic processes, and conversely how altering genetic processes changes blood flow, leading to hearts with defects. Results from this project will ultimately guide approaches to treat heart defects before a baby is born. To further broaden the impact of this project to the society, outreach activities involving rising high school sophomores, juniors, and seniors in California and Oregon, will engage the students in scientific activities with the goal of learning about heart development and cultivate team science skills. Although both blood flow and genetic processes contribute to heart development, how exactly they interact and affect each other, and the synergistic roles that blood flow and genetics play to predispose the heart to malformations are yet undetermined. The project’s intellectual merit is to elucidate interlinked connections between blood flow and genetic processes during heart development. More specifically, the project will study early changes in gene expression in response to altered blood flow, and early changes in blood flow in response to altered signaling, using two complementary avian models of heart development. The project will focus on three main objectives: (1) Determine blood flow and flow-induced stresses during normal and aberrant cardiac formation through advanced engineering methods; (2) Identify and quantify cellular responses to normal and perturbed heart development by generating spatiotemporal maps of cardiac adaptation; and (3) Determine the genetic and epigenetic adaptations in cardiac tissues due to early perturbations by DNA methylation and RNA sequencing. As the broader impact, results from this project will ultimately guide fundamental knowledge on embryonic heart development and help devise strategies to improve diagnosis of heart defects, prevent heart malformations, and eventually guide early fetal interventions to ameliorate the adverse effects of cardiac defects.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.