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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：
10682556
负责人：
Alex Lammers
金额：
$ 1.93万
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 2024-01-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682556
关键词：
3-Dimensional Actins Adherens Junction Adhesives Affect Beds Binding Biological Biological Process Birds Blood Cells Blood Island Blood Vessels Blood capillaries CD45 Antigens Cell Communication Cells Circulation Clinical Complex Cues Development Devices Disease Embryo Embryonic Development Endothelial Cells Engineering Goals Heart In Vitro Intercellular Junctions Ischemia Island Left Light Liquid substance Mechanics Mediating Microfluidic Microchips Microfluidics Modeling Molecular Morphology Myocardial Ischemia National Heart, Lung, and Blood Institute Pathway interactions Pattern Peripheral arterial disease Phenotype Phosphoric Monoester Hydrolases Plasma Play Process Proliferating Psychological reinforcement Regulation Reporting Research Rest Role Signal Transduction Strategic vision Structure Techniques Therapeutic Thinness Time Tissues Transmembrane Domain Tube Vascular Diseases Vascular remodeling Vascularization Viscosity Zebrafish cadherin 5 capillary bed cardioprotection effective therapy egg experimental study gamma secretase healthy aging in vivo in vivo Model insight mechanotransduction nervous system disorder notch protein novel promote resilience protein expression receptor resilience response shear stress vascular contributions vasculogenesis vector

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).

项目总结/文摘