The Glycocalyx and Endothelial Barrier Regulation

糖萼和内皮屏障调节

• 批准号: 6619794
• 负责人: randal Owen dull
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-13 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619794
• 关键词: antisense nucleic acid; cell adhesion; cell component structure /function; cytoskeleton; gene expression; glycolipids; glycoprotein biosynthesis; glycoprotein structure; glycoproteins; heparan sulfate; immunofluorescence technique; immunoprecipitation; northern blottings; polysaccharides; protein protein interaction; protein structure function; sialate; syndecan; thrombin; tight junctions; tissue /cell culture; vascular endothelium; vascular endothelium permeability; western blottings

Increased vascular permeability remains a critical determinant of morbidity and mortality in the ICU. There is overwhelming evidence that the endothelial glycocalyx plays an important role in determining the permeability of the microvascular wall. This surface layer is composed of entangled chains of proteoglycans, glycoproteins and adsorbed serum proteins that contribute to the formation of a `fiber-- matrix'. Experimental data regarding the structure-function relationship between surface glycoproteins and endothelial barrier properties is limited. The purpose of the proposed studies is to investigate the structure-function relationship of selected glycoproteins, which are major components of the endothelial glycocalyx, and their role in modulating endothelial barrier function. We hypothesize that cell-surface glycoproteins regulate endothelial barrier integrity by: 1) comprising the primary molecular sieve that determines microvascular permeability to water and serum proteins and, 2) through cytoskeletal interactions which modulate cell-cell adhesion, adherens junction organization, focal adhesion formation and, therefore, endothelial barrier function. Specific Aim #1 will define the contribution of specific glycoprotein components on endothelial barrier function. Specific Aim #2 will characterize the effect of altered expression of selected glycoproteins on endothelial barrier function. In Specific Aim #3 we will characterize the interaction of selected glycoproteins with the cytoskeletal and adherens junction proteins. Finally, In Specific Aim #4 we characterize the role of gycoproteins as shear stress sensors The PI, Dr. Randal Dull is committed to a career in academic medicine and research and to understanding the role of the glycocalyx in endothelial barrier regulation; this knowledge may lead to new therapeutic strategies to treat capillary leak syndrome. For example, novel resuscitation fluids composed of synthetic colloids could be developed that exploit cell-surface glycoprotein binding in order to normalize capillary permeability. This K08 will provide the foundation for a research career dedicated to understanding the molecular mechanisms of endothelial barrier regulation.

血管通透性增加仍然是 ICU 发病率和死亡率的关键决定因素。大量证据表明内皮糖萼在决定微血管壁的通透性方面发挥着重要作用。该表面层由蛋白聚糖、糖蛋白和吸附的血清蛋白的缠结链组成，有助于形成“纤维基质”。关于表面糖蛋白和内皮屏障特性之间的结构-功能关系的实验数据是有限的。本研究的目的是研究选定的糖蛋白（内皮糖萼的主要成分）的结构-功能关系，以及它们在调节内皮屏障功能中的作用。我们假设细胞表面糖蛋白通过以下方式调节内皮屏障完整性：1）包含决定微血管对水和血清蛋白通透性的主要分子筛，2）通过细胞骨架相互作用调节细胞间粘附、粘附连接组织、粘着斑形成，从而调节内皮屏障功能。具体目标#1 将定义特定糖蛋白成分对内皮屏障功能的贡献。具体目标#2 将描述所选糖蛋白的表达改变对内皮屏障功能的影响。在特定目标#3 中，我们将表征所选糖蛋白与细胞骨架和粘附连接蛋白的相互作用。最后，在具体目标#4中，我们描述了糖蛋白作为剪切应力传感器的作用。这些知识可能会带来治疗毛细血管渗漏综合征的新治疗策略。例如，可以开发由合成胶体组成的新型复苏液，利用细胞表面糖蛋白结合来使毛细血管通透性正常化。该 K08 将为致力于了解内皮屏障调节分子机制的研究生涯奠定基础。