Local Regulation of Angiogenesis by Microenvironment

项目说明和总结 工程化组织的血管化是组织最终成功的关键 工程学作为一种器官替代疗法。新的毛细血管的形成 来自现有的血管系统，或血管生成，也与 许多疾病，包括癌症，并由组织内的局部线索调节 微环境。这个重建项目的总体目标是了解 局部细胞外基质(ECM)特性调控内皮细胞的机制 血管生成所需的侵袭和萌芽形态发生，并利用这些见解 指导临床相关生物材料的设计以促进血管生成 申请。研究人员发现，与ECM的粘连不仅会产生 生化，但也有机械信号，这些信号在驱动内皮细胞方面很重要 功能。研究人员的初步研究表明，细胞外基质的硬度， 黏附性和降解性可用于调节血管新生侵袭。 通过调节关键信号通路来调节这些材料的过程 肌动蛋白细胞骨架。在这项提案中，调查员提议进一步调查 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，以研究不同基质属性和 它们在使用体外和体内模型调控血管生成方面的合作，以及 观察这些材料内血管发育的形态动力学。这个 调查人员将检查这些材料是否可以用来控制 血管新生血管的结构。总之，这些研究将确定这些机制 ECM中的局部结构和机械特性通过什么来调节内皮细胞 细胞功能和毛细血管形态发生，并建立新的生物材料设计 促进体外工程组织和天然组织血管生成的策略 缺血组织。

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.