Local Regulation of Angiogenesis by Microenvironment

微环境对血管生成的局部调节

基本信息

批准号：
10152652
负责人：
CHRISTOPHER S CHEN
金额：
$ 36.38万
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：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152652
关键词：
3-Dimensional Actins Adhesions Adhesiveness Adhesives Angiogenic Factor Apoptosis Architecture Automobile Driving Behavior Binding Biochemical Biocompatible Materials Blood Vessels Blood capillaries Capillary Endothelial Cell Cell Adhesion Cell physiology Cells Chemicals Chronic Complex Cues Cytoskeleton Development Devices Disease Endothelial Cells Engineering Engraftment Environment Equilibrium Extracellular Matrix Failure Gene Expression Goals Grant Growth Growth Factor Human body Implant In Vitro Invaded Investigation Ischemia Link Malignant Neoplasms Mechanics Mediating Methods Morphogenesis Movement Nutrient Organ Oxygen Pathogenesis Pathology Pattern Perfusion Play Positioning Attribute Postoperative Period Process Property Receptor Signaling Recovery Regulation Replacement Therapy Research Research Personnel Role Signal Pathway Signal Transduction Structure Testing Tissue Engineering Tissues Translating Vascular Diseases Vascularization angiogenesis clinically relevant crosslink design diabetic improved in vivo in vivo Model insight mechanical properties notch protein novel physical property response rho success three-dimensional modeling tumor growth

项目摘要

Project Description and Summary The vascularization of engineered tissues is critical to the ultimate success of tissue engineering as an organ replacement therapy. The formation of new capillary vessels from existing vasculature, or angiogenesis, also is linked to the pathogenesis of numerous diseases including cancer, and is regulated by local cues within the tissue microenvironment. The general goal of this renewal project is to understand the mechanism by which local extracellular matrix (ECM) properties regulate endothelial cell invasion and sprout morphogenesis required in angiogenesis, and to use these insights to guide design of biomaterials to enhance angiogenesis for clinically relevant applications. The investigator has found that adhesion to ECM generates not only biochemical, but also mechanical signals that are important in driving endothelial cell function. Preliminary studies from the investigator suggest that ECM stiffness, adhesiveness, and degradability could be used to regulate the angiogenic invasion process through such materials by modulating key signaling pathways regulating the actin cytoskeleton. In this proposal, the investigator proposes to further investigate the role of these ECM cues in regulating angiogenic behaviors. The project proposes to develop biomaterials to investigate the contributions of different matrix properties and their cooperation in regulating angiogenesis using both in vitro and in vivo models, and to examine the morphodynamics of developing vasculature within those materials. The investigator will examine whether these materials can be used to control the architecture of angiogenic vessels. Together, these studies will define the mechanisms by which local structural and mechanical properties within ECM modulate endothelial cell function and capillary morphogenesis, and establish new biomaterials design strategies to promote angiogenesis in ex-vivo engineered tissues as well as native ischemic tissues.

项目描述和总结工程组织的血管化对于组织的最终成功至关重要工程作为器官替代疗法。新毛细血管的形成来自现有脉管系统或血管生成，也与以下疾病的发病机制有关：包括癌症在内的许多疾病，并受到组织内局部信号的调节微环境。该更新项目的总体目标是了解局部细胞外基质（ECM）特性调节内皮细胞的机制血管生成所需的侵袭和发芽形态发生，并利用这些见解指导生物材料的设计，以增强临床相关的血管生成应用程序。研究人员发现 ECM 的粘附不仅产生对驱动内皮细胞很重要的生化信号和机械信号功能。研究人员的初步研究表明 ECM 硬度，粘附性和降解性可用于调节血管生成侵袭通过调节关键信号通路来处理这些材料肌动蛋白细胞骨架。在该提案中，研究者建议进一步调查这些 ECM 信号在调节血管生成行为中的作用。该项目建议开发生物材料来研究不同基质特性的贡献和他们使用体外和体内模型在调节血管生成方面的合作，以及检查这些材料内发育的脉管系统的形态动力学。这调查员将检查这些材料是否可以用于控制血管生成血管的结构。这些研究将共同确定其机制 ECM 内的局部结构和机械特性通过其调节内皮细胞细胞功能和毛细血管形态发生，并建立新的生物材料设计促进离体工程组织以及天然组织中血管生成的策略缺血组织。