The Glycocalyx and Endothelial Barrier Regulation

糖萼和内皮屏障调节

• 批准号: 6527790
• 负责人: randal Owen dull
• 金额: $ 13.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527790
• 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。有压倒性的证据表明，内皮糖萼在决定微血管壁的通透性方面起着重要作用。这一表层由纠缠在一起的蛋白聚糖链、糖蛋白和吸附的血清蛋白组成，它们有助于形成“纤维基质”。关于表面糖蛋白与内皮屏障特性之间结构-功能关系的实验数据有限。本研究的目的是研究作为内皮糖萼主要组成部分的糖蛋白的结构-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的完整性：1)组成决定微血管对水和血清蛋白渗透性的主要分子筛；2)通过调节细胞-细胞粘附、粘附连接组织、局灶粘附形成以及内皮屏障功能的细胞骨架相互作用。Specific Aim #1将定义特定糖蛋白组分对内皮屏障功能的贡献。特异性目标#2将描述选定糖蛋白表达改变对内皮屏障功能的影响。在Specific Aim #3中，我们将描述选定的糖蛋白与细胞骨架和粘附体连接蛋白的相互作用。最后，在Specific Aim #4中，我们描述了糖蛋白作为剪切应力传感器的作用。PI， Randal Dull博士致力于学术医学和研究的职业生涯，并了解糖萼在内皮屏障调节中的作用；这些知识可能会导致新的治疗策略来治疗毛细血管渗漏综合征。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。这个K08将为致力于理解内皮屏障调节的分子机制的研究生涯提供基础。