Fluid shear stress mechanotransduction at endothelial cell-cell junctions

内皮细胞-细胞连接处的流体剪切应力机械转导

基本信息

批准号：
10688712
负责人：
Chenxiang Lin
金额：
$ 8.46万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-27 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688712
关键词：
Address Adhesions Adult African American Atherosclerosis Biochemical Blood Vessels Blood flow Cells Collaborations Complex DNA Data Development Disease Doctor of Philosophy Education Educational workshop Embryonic Development Endothelial Cells Extracellular Domain Family Funding G-Protein-Coupled Receptors GPSM2 gene Genes Genetic Polymorphism Goals Hypertension In Vitro Intercellular Junctions International Investigation Ischemic Stroke KDR gene Knockout Mice Learning Link Liquid substance Mechanical Stress Membrane Proteins Mentorship Methods Molecular Molecular Conformation Mus Pathway interactions Physiological Physiology Proteins Publishing Receptor Protein-Tyrosine Kinases Role Signal Transduction Site Structure Vascular Diseases Vascular Endothelial Cell adhesion receptor alpha-latrotoxin receptor cadherin 5 conformational conversion experimental study in vivo insight laboratory experience malformation mechanotransduction meetings nanodevice novel parent grant parent project shear stress

项目摘要

Summary of the funded parent grant The goal of our project “Fluid shear stress mechanotransduction at endothelial cell-cell junctions” is to elucidate mechanisms by which vascular endothelial cells sense fluid shear stress (FSS) from blood flow, which is a major determinant of blood vessel embryonic development, adult physiology and multiple diseases including atherosclerosis and vascular malformations. While a great many pathways and genes that respond to FSS have been identified, major questions about fundamental molecular mechanisms by which cell convert FSS into biochemical information remain unanswered. The project is based on published and preliminary data showing that cell-cell junctions are a major site of shear stress mechanotransduction via a complex of membrane proteins consisting of the homophilic adhesion receptors PECAM-1 (hereafter PECAM) and VE- cadherin, and the receptor tyrosine kinases VEGF receptor 2 and 3. More recently, we have identified the adhesion GPCR latrophilin1 (ADGRL2) as another junctional protein that appears to be the initial upstream trigger that activates the junctional pathway [1]. This pathway is highly relevant to vascular disease as polymorphisms in PECAM-1 are linked to atherosclerosis, while ADGRL2 is linked to hypertension and ischemic stroke.

资助的父母赠款的摘要我们项目“内皮细胞 - 细胞连接处的流体剪切应力机械转导的目标”的目的是阐明血管内皮细胞从血流中感知流体剪切应力（FSS）的机制，这是血管胚胎发育，成人生理和多种疾病的主要决定包括动脉粥样硬化和血管畸形。虽然有很多回应的途径和基因已经确定了FSS，有关细胞转换的基本分子机制的主要问题 FSS进入生化信息仍未得到解决。该项目基于已发布和初步数据表明细胞细胞连接是通过由均电受体PECAM-1（以下称PECAM）和VE-组成的膜蛋白钙粘蛋白和受体酪氨酸激酶VEGF受体2和3。最近，我们已经确定了粘附GPCR Latrophilin1（ADGRL2）作为另一种连接蛋白，似乎是初始上游激活连接途径的触发[1]。该途径与血管疾病高度相关 PECAM-1中的多态性与动脉粥样硬化有关，而ADGRL2与高血压和缺血性中风。