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.

项目概要/摘要 内皮表面糖萼（ESG）是血管内皮上富含碳水化合物的层。 ESG 是 由膜糖蛋白、糖胺聚糖和蛋白聚糖组成，形成一个庞大的基质状结构 在血流机械转导、内皮细胞维持中发挥关键功能的结构 通透性以及白细胞粘附和炎症的控制。最重要的常态之一 ESG 的生理功能是介导机械传导，导致钙离子的摄入和 响应血流而产生一氧化氮 (NO)。 ESG 机械转导功能失调 发现于心血管疾病，如脓毒症、缺血再灌注、高血压和糖尿病。虽然 ESG 在心血管疾病中的重要作用已经确定，其生物力学特性，如 以及其正常机械转导的机制尚未得到阐明。这种缺乏 进步在很大程度上归因于分子和分子中发生的机械力和反应。 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 建议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 的力传导特性。我们将描述 ESG 介导的潜在机制 使用新型原子力显微镜 (AFM) 荧光在单细胞水平上进行机械转导 显微镜方法。拟议的研究将更清楚地了解 ESG 介导的 机械传导功能，对 ESG 相关疾病具有重要意义，例如脓毒症、 缺血再灌注、糖尿病和高血压及其治疗。