Dynamic regulation of embryonic endothelial cell migration in response to hemodynamic force

胚胎内皮细胞迁移响应血流动力学的动态调节

基本信息

批准号：
10629238
负责人：
Mary E Dickinson
金额：
$ 49.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10629238
关键词：
Acute Affect Arteries Arteriovenous malformation Automobile Driving Biosensor Blood Vessels Blood capillaries Blood flow Caliber Cardiac Cardiovascular system Cells Cessation of life Circulation Complement Data Defect Development Diameter Embryo Endothelial Cells Endothelium FOXO1A gene Future Gene Expression Genes Genetic Transcription Growth Image Investigation Lead Methods Microscopy Modeling Morphology Mus Mutation Notch Signaling Pathway Pathway interactions Phosphotransferases Population Process Regulation Reporter Research Personnel Signal Transduction Specific qualifier value Testing Three-Dimensional Imaging Time Tissues Trees Uncertainty Work Yolk Sac angiogenesis cell motility cofactor conditional knockout directional cell experimental study fetal gain of function hemodynamics human disease loss of function mechanical signal mechanical stimulus migration mouse model new technology notch protein novel optogenetics pharmacologic polarized cell response sensor shear stress single-cell RNA sequencing transcriptome sequencing transcriptomic profiling transcriptomics

项目摘要

PROJECT SUMMARY To accommodate the demands of the constantly expanding embryo, vessels of the fetal circulatory system must undergo extensive morphological remodeling while simultaneously supporting pre-existing tissues. Mechanical stimuli, generated by the hemodynamic force, are critical regulators of this process, driving adaptive responses to blood flow such as vessel fusion, widening, or regression. Herein, we propose experiments to determine how early vessels remodel in response to changes in blood flow. Our hypothesis is that differential activation of a Flk1/ERK/Dll4/Notch signaling axis creates a subset of ECs competent to respond to blood flow, resulting in the directed migration and expansion of the vitelline artery. We have assembled an outstanding team of investigators, as well as novel technologies, mouse models and methods to test this hypothesis in three specific aims: 1. Use loss- and gain-of-function models of Flk1/ERK/Dll4/Notch signaling to define differences in endothelial cell (EC) migration during vessel remodeling. 2. Use a real-time ERK biosensor to determine whether ECs that migrate in response to changes in blood flow upregulate ERK activity and if altering ERK signaling, or modulating blood flow, affects cell migration. 3. Employ single cell RNA-sequencing to determine if a specific population of cells exists in the VA with high arterial gene expression and elevated levels of polarization and pro-migratory genes. The transcriptional data will complement the dynamic, 3D imaging data, allowing us to reveal the network of factors required in specialized ECs that would otherwise be lost through studies at a population level (e.g. via bulk RNA-seq) and will no doubt prompt novel future investigation into hemodynamic force signaling and EC migration in the embryo.

项目概要为了适应不断扩大的胚胎的需求，胎儿循环系统的血管必须经历广泛的形态重塑，同时支持预先存在的组织。机械的由血流动力学产生的刺激是这一过程的关键调节器，驱动适应性反应血流，例如血管融合、扩张或退化。在此，我们提出实验来确定早期血管如何响应血液变化而重塑流动。我们的假设是 Flk1/ERK/Dll4/Notch 信号轴的差异激活会产生 ECs 的子集能够对血流做出反应，从而导致定向迁移和扩张卵黄动脉。我们组建了一支优秀的研究团队以及新颖的技术，小鼠模型和方法在三个具体目标上检验这一假设： 1. 使用功能丧失和获得功能 Flk1/ERK/Dll4/Notch 信号传导模型，用于定义血管过程中内皮细胞 (EC) 迁移的差异重塑。 2. 使用实时 ERK 生物传感器来确定 EC 是否会响应环境变化而迁移血流上调 ERK 活性，如果改变 ERK 信号传导或调节血流，则会影响细胞迁移。 3. 采用单细胞 RNA 测序来确定 VA 中是否存在具有高动脉基因表达以及极化和促迁移基因水平升高。转录数据将补充动态 3D 成像数据，使我们能够揭示所需的因素网络专门的 EC，否则这些 EC 会通过群体水平的研究（例如通过批量 RNA-seq）而丢失，以及毫无疑问，这将促进未来对胚胎中血流动力学信号和 EC 迁移的新研究。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FOXO1 represses sprouty 2 and sprouty 4 expression to promote arterial specification and vascular remodeling in the mouse yolk sac.

FOXO1 抑制 sprouty 2 和 sprouty 4 的表达，以促进小鼠卵黄囊中的动脉规范和血管重塑。

DOI：
10.1242/dev.200131
发表时间：
2022
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Li-Villarreal,Nanbing;Wong,RebeccaLeeYean;Garcia,MonicaD;Udan,RyanS;Poché,RossA;Rasmussen,TaraL;Rhyner,AlexanderM;Wythe,JoshuaD;Dickinson,MaryE
通讯作者：
Dickinson,MaryE

Three-dimensional microCT imaging of mouse heart development from early post-implantation to late fetal stages.

DOI：
10.1007/s00335-022-09976-7
发表时间：
2023-06
期刊：
MAMMALIAN GENOME
影响因子：
2.5
作者：
Li-Villarreal, Nanbing;Rasmussen, Tara L.;Christiansen, Audrey E.;Dickinson, Mary E.;Hsu, Chih-Wei
通讯作者：
Hsu, Chih-Wei