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

• 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
• 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

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).

项目概要/摘要 毛细血管丛形成的机制已在鸟类、斑马鱼和哺乳动物胚胎中得到充分研究， 这些过程的精确时间被发现对于形成 高效且强大的脉管系统。但由于体内发育模型的限制，目前尚无结果。 修改初始条件或暂时修改流动的起始以及增加粘度的重要性 血细胞何时进入循环尚不清楚。最近的报告利用了可用的精确控制 在微流体体外装置中阐明新的血管生成机制。本提议的目标 研究的目的是确定如何暂时调节剪切应力、介质粘度和增加皮质 通过非典型Notch途径的肌动蛋白组装影响新生毛细血管床向毛细血管床的转变 对齐静态血管网络，并确定导致从稳定转变的分子线索 静态网络转变为高度动态的表型。实验将在体外双通道中进行 微流体装置可精确控制体内模型中无法实现的实验条件。整体 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，能够实现快速有效的血管重塑，这是稳定的 皮质强化非典型Notch通路。我们将解决这个假设并实现 通过首先确定精确定时的剪切力、动态粘度变化以及添加 新生脉管系统上的外源蛋白表达影响皮质强化、网络动态和 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​​应改变的流量剖面中的Notch信号。改变施加的力的后果 血管岛和新生脉管系统以及它如何允许血管网络重塑将被确定， 并确定抑制皮质-Notch 通路的部分部分是否可以使网络恢复正常状态 稳定静止到高度动态和增殖，而不损害规范的整体表达 缺口表达。更全面地了解这一过程具有重要的生物学和临床意义 因为它将为高度流行和致命的血管疾病（例如外周血管疾病）提供新的恢复疗法 动脉疾病（PAD）和缺血性心脏病（IHD）。