Regulation of the Endothelial Cell Glycocalyx

内皮细胞糖萼的调节

• 批准号: 6999302
• 负责人: BRIAN R DULING
• 金额: $ 37.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999302
• 关键词: adenosine; biological signal transduction; blood vessel disorder; cell component structure /function; cell wall; electron microscopy; fluorescence microscopy; genetically modified animals; ischemia; laboratory mouse; microcirculation; purinergic receptor; shear stress; tumor necrosis factor alpha; vascular endothelium; vascular endothelium permeability; vasoconstrictors; vasodilators; wild animals

DESCRIPTION (provided by applicant): In recent years the endothelial cell glycocalyx has been shown to play a pivotal role in microvessel function by modulating rheology, permeability, and leukocyte-endothelial cell interactions. We now propose to extended those observations with the hypothesis that the glycocalyx is a dynamic structure, which is regulated and that pathophysiological stimuli can cause its degradation and disorganization, which will contribute to enhanced intimal permeability, platelet adhesion, accelerated white cell binding, and emigration of white cells from the vasculature. In vivo video microscopy allows us to follow changes in the microcirculation in response to stimuli, and microperfusion allows us to mark the glycocalyx and to selectively treat small, localized segments of the microcirculation. We propose two experimental aims which will place the role of the glycocalyx in endothelial cell function on a much firmer footing, and which will set the groundwork for an understanding of the role for the glycocalyx in pathophysiology. Specific Aim #1 - to test and explore the hypothesis that the glycocalyx is an adaptive component of the vascular wall, and that it is a key potential site for damage. The following questions will be answered to test the hypothesis. 1. Do vasoactive substances alter the glycocalyx by modifying wall shear stress? 2. Do inflammatory stimuli exert a common set of effects on the size and permeability of the glycocalyx? Specific Aim #2 - to test the hypothesis that one of the key sequences of events in response to ischemia/reperfusion is the activation of adenosine receptors and their primary and/or secondary effects on the glycocalyx. The following questions will be answered to test the hypothesis. 1. Can the effects of ischemia/reperfusion on the glycocalyx be reduced by activation of the adenosine A2A receptor? 2. Can the effects of I/R be mimicked by activation of A3 receptors? 3. Are the detrimental effects of large doses of adenosine mediated though actions on mast cells, leukocytes, or endothelial cells? The proposal is based on the use of recently developed highly potent and selective adenosine blockers, and a group of genetically engineered animals. The experiments offer the potential for understanding a new level of microvascular regulation, and for developing strategies to understand the intracellular signaling that leads to modification of the glycocalyx.

描述（由申请人提供）：近年来，内皮细胞糖萼已被证明通过调节流变性、渗透性和白细胞-内皮细胞相互作用在微血管功能中发挥关键作用。我们现在建议扩展这些观察结果，假设糖萼是一种动态结构，受到调节，病理生理刺激可导致其降解和解体，这将有助于增强内膜通透性、血小板粘附、加速白细胞结合和迁移来自脉管系统的白细胞。体内视频显微镜使我们能够跟踪微循环对刺激的反应变化，而微灌注使我们能够标记糖萼并选择性地治疗微循环的小局部片段。我们提出了两个实验目标，这将为糖萼在内皮细胞功能中的作用奠定更坚实的基础，并为理解糖萼在病理生理学中的作用奠定基础。 具体目标#1 - 测试和探索以下假设：糖萼是血管壁的适应性组成部分，并且是潜在损伤的关键部位。将回答以下问题来检验假设。 1. 血管活性物质是否通过改变壁剪切应力来改变糖萼？ 2. 炎症刺激是否对糖萼的大小和渗透性产生一系列共同的影响？ 具体目标#2 - 检验以下假设：响应缺血/再灌注的关键事件序列之一是腺苷受体的激活及其对糖萼的主要和/或继发影响。将回答以下问题来检验假设。 1. 激活腺苷A2A受体可以减少缺血/再灌注对糖萼的影响吗？ 2. I/R 的作用可以通过 A3 受体的激活来模拟吗？ 3. 大剂量腺苷的有害影响是通过对肥大细胞、白细胞或内皮细胞的作用介导的吗？该提案基于使用最近开发的高效和选择性腺苷阻滞剂以及一组基因工程动物。这些实验为了解微血管调节的新水平以及制定策略来了解导致糖萼修饰的细胞内信号传导提供了潜力。