Elucidating Mechanisms for Rapid Vascularization by Modeling Vascular Islands in Early Embryogenesis

通过模拟早期胚胎发生中的血管岛来阐明快速血管化的机制

基本信息

批准号：
10313257
负责人：
Alex Lammers
金额：
$ 4.85万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313257
关键词：
3-Dimensional Actins Address Adherens Junction Adhesives Affect Beds Binding Biological Biological Process Birds Blood Cells Blood Circulation Blood Island Blood Vessels Blood capillaries CD45 Antigens Cell Communication Cells Clinical Complex Cues Development Devices Disease Embryo Embryonic Development Endothelial Cells Engineering Goals Heart In Vitro Intercellular Junctions Island Left Light Liquid substance Mechanics Mediating Microfluidic Microchips Microfluidics Modeling Molecular Morphology Myocardial Ischemia National Heart, Lung, and Blood Institute Neurologic Pathway interactions Pattern Peripheral arterial disease Phenotype Phosphoric Monoester Hydrolases Plasma Play Process Psychological reinforcement Regulation Reporting Research Rest Role Signal Transduction Techniques Therapeutic Thinness Time Tissues Transmembrane Domain Tube Vascular Diseases Vascular remodeling Vascularization Viscosity Vision Zebrafish cadherin 5 capillary bed cardioprotection effective therapy egg experimental study gamma secretase healthy aging in vivo in vivo Model insight mechanotransduction notch protein novel protein expression receptor resilience response shear stress vascular contributions vasculogenesis vector

3-Dimensional Actins Address Adherens Junction Adhesives Affect Beds Binding Biological Biological Process Birds Blood Cells Blood Circulation Blood Island Blood Vessels Blood capillaries CD45 Antigens Cell Communication Cells Clinical Complex Cues Development Devices Disease Embryo Embryonic Development Endothelial Cells Engineering Goals Heart In Vitro Intercellular Junctions Island Left Light Liquid substance Mechanics Mediating Microfluidic Microchips Microfluidics Modeling Molecular Morphology Myocardial Ischemia National Heart, Lung, and Blood Institute Neurologic Pathway interactions Pattern Peripheral arterial disease Phenotype Phosphoric Monoester Hydrolases Plasma Play Process Psychological reinforcement Regulation Reporting Research Rest Role Signal Transduction Techniques Therapeutic Thinness Time Tissues Transmembrane Domain Tube Vascular Diseases Vascular remodeling Vascularization Viscosity Vision Zebrafish cadherin 5 capillary bed cardioprotection effective therapy egg experimental study gamma secretase healthy aging in vivo in vivo Model insight mechanotransduction notch protein novel protein expression receptor resilience response shear stress vascular contributions vasculogenesis vector

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项目摘要

Project Summary/Abstract Mechanisms of capillary plexus formation have been well studied in avian, zebrafish, and mammalian embryos, with the precise timing of these processes being found to have profound importance in the formation of an efficient and robust vasculature. However, due to the limitations of in vivo developmental models, no results of modifying initial conditions or temporally modifying the initiation of flow and the importance of increased viscosity when blood cells enter circulation are unknown. Recent reports have leveraged the precise control available within microfluidic in vitro devices to elucidate novel angiogenic mechanisms. The objective of this proposed research is to determine how temporally modulating the shear stress, media viscosity, and increasing cortical actin assembly through a non-canonical Notch pathway affect the transition of a nascent capillary bed into an aligned quiescent vascular network, and determine the molecular cues that cause a transition from a stable quiescent network to a highly dynamic phenotype. Experiments will be carried out in an in vitro dual-channel microfluidic device to precisely control experimental conditions that are unavailable in in vivo models. The overall hypothesis of this proposal is that changes in shear force and fluid viscosity initiated immediately after formation of the primitive plexus, enable rapid and efficient vascular remodeling, which is stabilized by a cortical reinforcing non-canonical Notch pathway. We will address this hypothesis and achieve the proposed goals by first determining how precisely timed shear force, dynamic viscosity changes, and addition of exogenous protein expression on nascent vasculature affects cortical reinforcement, network dynamics, and morphology. Secondly, we will elucidate the main molecular and mechanotransduction mediated role of cortical- Notch signaling in network adaptation to altered flow profiles. The ramifications of altered force applied to vascular islands and a nascent vasculature and how it allows vascular network remodeling will be determined, and ascertain whether inhibition of parts of the cortical-Notch pathway allows the network to revert from being stably quiescent to highly dynamic and proliferative without compromising the overall expression of canonical- Notch expression. More complete understanding of this process is of significant biological and clinical importance as it will allow novel restorative therapies for highly prevalent and deadly vascular diseases such as Peripheral Arterial Disease (PAD) and Ischemic Heart Disease (IHD).

项目摘要/摘要毛细血管形成的机理在鸟类，斑马鱼和哺乳动物胚胎中已经进行了很好的研究，由于这些过程的确切时机被发现在形成中具有极大的重视有效而健壮的脉管系统。但是，由于体内发展模型的局限性，没有修改初始条件或时间修改流量的启动以及粘度提高的重要性当血细胞进入循环时，未知。最近的报告利用了可用的确切控制在微流体内的体外装置中，以阐明新型的血管生成机制。该提议的目的研究是为了确定如何调节剪切应力，培养基粘度和增加皮质肌动蛋白通过非典型凹口途径会影响新生毛细管床的过渡对齐静止的血管网络，并确定导致从稳定的过渡的分子提示静态网络具有高度动态的表型。实验将在体外双通道中进行微流体设备可以精确控制体内模型中无法使用的实验条件。总体该提议的假设是，剪切力和流体粘度的变化立即开始原始丛的形成，可以使快速有效的血管重塑，并稳定皮质增强非经典凹口途径。我们将解决这一假设，并实现通过首先确定精确定时的剪切力，动态粘度变化以及添加外源性蛋白质在新生脉管系统上的表达会影响皮质增强，网络动力学和形态学。其次，我们将阐明皮质的主要分子和机械转导介导的作用网络适应更改流量轮廓的Notch信号传导。施用的改变的后果血管岛和新生的脉管系统以及如何确定其允许血管网络重塑的方法并确定抑制皮层途径的部分是否使网络恢复为稳定地对高度动态和增殖，而不会损害规范的总体表达缺口表达。对这一过程的更完整了解具有重要的生物学和临床重要性因为它将允许新颖的恢复性疗法用于高度流行和致命的血管疾病，例如周围动脉疾病（PAD）和缺血性心脏病（IHD）。