Single-cell analysis of endothelial mechanotransduction mediated by endothelial surface glycocalyx

内皮表面糖萼介导的内皮机械转导的单细胞分析

• 批准号: 10733119
• 负责人: Xiaohui Zhang
• 金额: $ 5.07万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10733119
• 关键词: Single; cell; analysis; endothelial; mechanotransduction

PROJECT SUMMARY/ABSTRACT Endothelial surface glycocalyx (ESG) is a carbohydrate-rich layer found on vascular endothelium. ESG is composed of membrane glycoproteins, glycosaminoglycans and proteoglycans, forming a bulky, matrix-like structure that serves critical functions in mechanotransduction of blood flow, maintenance of the endothelial permeability, and the control of leukocyte adhesion and inflammation. One of the most important normal physiological functions of ESG is to mediate mechanotransduction that leads to the intake of calcium ions and the production of Nitric Oxide (NO) in response to blood flow. Dysfunctional ESG mechanotransduction has been found in cardiovascular diseases such as sepsis, ischemia-reperfusion, hypertension, and diabetes. While the critical involvement of ESG in cardiovascular diseases has been established, its biomechanical properties, as well as the mechanisms underlying its normal mechanotransduction, have resisted elucidation. This lack of progress is due in large part to the fact that mechanical forces and responses that occur at the molecular and sub-cellular levels are transient, minute and therefore difficult to trace and measure. The goal of the current proposal is to develop new research tools and model systems and use them to uncover the biomechanical and mechanotranduction properties of ESG. We will characterize mechanisms underlying ESG-mediated mechanotransduction on a single-cell level using a novel Atomic Force microscopy (AFM)-fluorescence microscopy approach. The proposed study will achieve a clearer understanding of ESG-mediated mechanotransductory function, with important implications for ESG-related diseases, such as sepsis, ischemiareperfusion, diabetes and hypertension, and their therapeutics.

项目总结/摘要 内皮细胞表面糖萼（ESG）是血管内皮细胞表面富含碳水化合物的一层。ESG是 由膜糖蛋白、糖胺聚糖和蛋白聚糖组成，形成庞大的基质样 在血流的机械传导、内皮细胞的维持和血管内皮细胞的增殖中起关键作用的结构。 渗透性以及白细胞粘附和炎症的控制。其中最重要的正常 ESG的生理功能是介导导致钙离子摄入的机械传导， 一氧化氮（NO）的产生是对血流的反应。功能失调的ESG机械转导已经被证实是 在心血管疾病如败血症、缺血再灌注、高血压和糖尿病中发现。而 ESG在心血管疾病中的重要作用已经确立，其生物力学特性， 以及其正常的机械转导机制，一直拒绝阐明。这种缺乏 进展在很大程度上是由于这样的事实，即机械力和反应，发生在分子和 亚细胞水平是短暂的、微小的，因此难以追踪和测量。当前的目标 一项提案是开发新的研究工具和模型系统，并利用它们来揭示生物力学和 ESG的机械传导特性。我们将描述ESG介导的 使用新的原子力显微镜（AFM）-荧光在单细胞水平上进行机械转导 显微镜方法。这项研究将使我们对ESG介导的 机械传导功能，对ESG相关疾病具有重要意义，如败血症， 缺血再灌注、糖尿病和高血压，以及它们的治疗。