Blood Flow Regulation of Pharyngeal Arch Artery Morphogenesis

咽弓动脉形态发生的血流调节

基本信息

批准号：
1635712
负责人：
Jonathan Butcher
金额：
$ 45万
依托单位：
Cornell University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-02-28
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1635712&HistoricalAwards=false
关键词：
Blood Flow Regulation Pharyngeal Arch

项目摘要

Early embryonic heart outflow is delivered via symmetric pairs of vessels called the pharyngeal arch arteries. This vascular manifold remodels into portions of the pulmonary arteries, aorta, and other critical great vessels. Many children suffer from serious birth defects that have their origin in how this vascular network reorganizes, and can be immediately life threatening without complex surgical intervention. Few genes have been found that control these processes, suggesting that mechanical forces from blood flow influence local cellular signaling to control vessel growth and shape changes. Determining how pharyngeal arch artery growth is controlled is a key basic science need for understanding heart formation and potentially to help with heart regeneration. The research integrates novel computational and experimental approaches to quantitatively model and directly manipulate the profile of fluid forces in the developing pharyngeal arch arteries, and predict how these changes direct downstream vascular network remodeling and the maturation of the vascular walls. The research is targeted at producing a new strategy to diagnose and correct great vessel malformations before birth.This project will advance fundamental knowledge of how hemodynamic forces control multiscale remodeling of the embryonic pharyngeal arch artery network, the precursors to the cardiac outflow tract and great vessels. Novel technology enabling noninvasive visualization and occlusion of individual network vessels in live embryos is combined with computational fluid dynamics simulations that incorporate lumped parameter boundary conditions reflecting physiological boundary conditions. This project will test the overall hypothesis that conserved hemodynamic signatures within the pharyngeal arch artery network controls its local remodeling and maturation. Acute hemodynamic changes resulting from in vivo pharyngeal arch artery photo-occlusion will be correlated with downstream vascular network lumen growth and remodeling. These fluid forces will then be correlated with temporal changes in local vascular wall thickness, composition and phenotype. Finally, direct photo-ablation of occluded pharyngeal arch arteries will be used to restore hemodynamic signaling, and test whether this restores lineage patterning, and/or downstream vascular remodeling. By analyzing actual anatomy from multiple experiments rather than using a single consensus geometry, key information will be generated 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.

早期的胚胎心脏流出是通过称为咽弓动脉的对称的血管对称的。该血管歧管重塑为肺动脉，主动脉和其他关键大血管的一部分。许多儿童患有严重的先天缺陷，这些缺陷起源于这种血管网络如何重组，并且可以在没有复杂的手术干预的情况下立即威胁生命。很少有人发现控制这些过程，这表明血流的机械力会影响局部细胞信号传导以控制血管的生长和形状变化。确定如何控制咽弓动脉的生长是理解心脏形成并有可能帮助心脏再生的关键基础科学需求。该研究将新颖的计算和实验方法整合在一起，以定量模型并直接操纵发展中咽弓动脉中流体力的特征，并预测这些变化如何直接下游血管网络重塑和血管壁的成熟。这项研究的目的是制定一种新的策略来诊断和纠正出生前的巨大血管畸形。该项目将对血液动力学如何控制胚胎咽弓动脉网络的多尺度重塑，心脏流出动脉的前体进行基本了解。新型技术实现了活胚中的单个网络血管的非侵入性可视化和遮挡，与计算流体动力学模拟结合在一起，这些模拟结合了反映生理边界条件的集体参数边界条件。该项目将检验总体假设，即咽弓动脉网络中保守的血液动力学特征控制其局部重塑和成熟。由体内咽弓动脉光封闭引起的急性血液动力学变化将与下游血管网络流明的生长和重塑相关。然后，这些流体力将与局部血管壁厚度，组成和表型的时间变化相关。最后，将使用封闭的咽弓动脉的直接光燃烧来恢复血液动力学信号，并测试这是否恢复谱系图案和/或下游血管重塑。通过分析来自多个实验的实际解剖结构，而不是使用单个共识几何形状，将生成有关形态学结局对细胞组成和/或流动场中局部偏差的可变性的关键信息，并进一步公差对血液动力学信号传导的急性变化。