Regulation of the Endothelial Cell Glycocalyx

内皮细胞糖萼的调节

基本信息

批准号：
7163516
负责人：
BRIAN R DULING
金额：
$ 36.15万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/7163516
关键词：
Adenosine Adenosine A2A Receptor Adhesions Agonist Animals Binding Blood Platelets Blood Vessels Blood capillaries Cell Communication Cell physiology Characteristics Dextrans Dimensions Dose Dyes Electron Microscopy Electrons Emigrations Endothelial Cells Engineering Erythrocytes Event Fluorescence Microscopy Functional disorder Glycocalyx Histamine Indium Inflammatory Ischemia Knock-out Leukocytes Localized Measurement Mediating Microcirculation Modification Mus Penetration Permeability Physiological Physiological reperfusion Play Proteins Protocols documentation Rate Regulation Reperfusion Injury Reperfusion Therapy Reporting Rheology Role Signal Transduction Site Stimulus Structure Surface TNF gene Testing Thick Tissues Tracer Vasoconstrictor Agents Vasodilator Agents Video Microscopy Work adenosine receptor activation base capillary dextran foot in vivo mast cell receptor research study response shear stress size

项目摘要

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，内皮细胞糖脂已被证明通过调节流变学，渗透性和白细胞 - 内皮细胞相互作用，在微血管函数中起关键作用。现在，我们建议通过假设糖椰子是一种动态结构来扩展这些观察结果，该结构受调节，病理生理刺激会导致其降解和混乱，这将有助于增强的内膜渗透性，血浆粘附，加速白细胞结合，并从白细胞结合，以及来自白细胞的迁移。体内视频显微镜使我们能够跟踪微循环的变化，以响应刺激，而微灌注使我们能够标记糖脂蛋白并有选择地处理微循环的小局部片段。我们提出了两个实验目的，这些实验目标将使糖脂在内皮细胞功能中的作用在更牢固的基础上，这将为理解糖脂在病理生理学中的作用奠定基础。特定目的1-测试和探讨糖椰子是血管壁的适应性成分的假设，并且它是损害的关键潜在部位。将回答以下问题以检验该假设。 1。血管活性物质是否通过修饰壁剪应力来改变糖脂素？ 2。炎症刺激是否对糖脂的大小和渗透性产生了共同的影响？具体目的＃2-检验以下假设：响应缺血/再灌注的事件的关键序列之一是腺苷受体的激活及其对糖囊体的主要和/或次要影响。将回答以下问题以检验该假设。 1。通过腺苷A2A受体的激活来减少缺血/再灌注对糖脂的影响吗？ 2。可以通过A3受体的激活来模仿I/R的效果？ 3。大剂量的腺苷对肥大细胞，白细胞或内皮细胞的作用是否有害影响？该提案基于最近开发的高度有效和选择性腺苷阻滞剂以及一组基因工程动物。该实验为理解新水平的微血管调节提供了潜力，并制定了了解导致糖蛋白改变的细胞内信号传导的策略。