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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对称的血管对称为咽弓动脉。该血管歧管重塑成肺动脉、主动脉和其他关键大血管的部分。许多儿童患有严重的出生缺陷，其起源在于这种血管网络的重组方式，并且可以立即危及生命，而无需复杂的手术干预。很少有基因被发现控制这些过程，这表明来自血流的机械力影响局部细胞信号传导以控制血管生长和形状变化。确定咽弓动脉生长是如何控制的是理解心脏形成的关键基础科学，并可能有助于心脏再生。该研究整合了新的计算和实验方法，以定量建模和直接操纵发育中的咽弓动脉中的流体力的轮廓，并预测这些变化如何指导下游血管网络重塑和血管壁的成熟。该研究旨在为出生前诊断和纠正大血管畸形提供新的策略。该项目将推进血流动力学如何控制胚胎咽弓动脉网络（心脏流出道和大血管的前体）的多尺度重塑的基础知识。新技术，使非侵入性可视化和闭塞的个别网络血管在活胚胎结合计算流体动力学模拟，包括反映生理边界条件的集总参数边界条件。该项目将测试咽弓动脉网络内保存的血流动力学特征控制其局部重塑和成熟的总体假设。体内咽弓动脉光闭塞引起的急性血流动力学变化与下游血管网管腔生长和重塑相关。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，闭塞的咽弓动脉的直接光消融将用于恢复血液动力学信号传导，并测试这是否恢复谱系模式和/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结构，将生成关于细胞组成和/或流场中局部偏差的形态发生结果的可变性以及它们对血液动力学信号传导中急性变化的耐受性的关键信息。