Collaborative Research: Deciphering the Synergistic Interaction Between Hemodynamics and Genetics that form the Heart

在心脏发育的早期，血流和遗传过程相互影响，以确保形成有效的心脏。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，在很大程度上仍然是未知的。加州大学欧文分校(UCI)和俄勒冈健康与科学大学(OHSU)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血流变化如何影响编程的遗传过程，反过来，改变遗传过程如何改变血液流动，从而导致心脏缺陷。该项目的结果最终将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，加州和俄勒冈州正在崛起的高二、大三和大四学生参加的外展活动将使学生参与科学活动，目的是了解心脏发育并培养团队科学技能。虽然血流和遗传过程都有助于心脏发育，但它们究竟是如何相互作用和影响的，以及血流和遗传在使心脏易患畸形方面所起的协同作用尚不确定。该项目的学术价值在于阐明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，该项目将使用两个互补的心脏发育鸟类模型，研究血液流动变化时基因表达的早期变化，以及信号变化时血液流动的早期变化。该项目将集中于三个主要目标：(1)通过先进的工程方法确定正常和异常心脏形成期间的血流和血流诱导的压力；(2)通过生成心脏适应的时空图，识别和量化细胞对正常和扰动心脏发育的反应；以及(3)通过DNA甲基化和RNA测序确定心脏组织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，该项目的结果最终将指导胚胎心脏发育的基本知识，并帮助制定策略，以改进心脏缺陷的诊断，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利影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力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.