Hemodynamic Adaptation of Intercellular Junctions in Human Endothelium

人内皮细胞间连接的血流动力学适应

基本信息

批准号：
7583964
负责人：
Brett R Blackman
金额：
$ 36.55万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583964
关键词：
Address Adherens Junction Apolipoprotein E Arteries Atherosclerosis Behavior Binding Proteins Biochemical Biophysics Blood Circulation Blood Vessels Blood capillaries Blood flow CD31 Antigens Cell Culture Techniques Cell Nucleus Cells Characteristics Complex Confocal Microscopy Cytoplasmic Tail Cytoskeleton Data Dependence Development Devices Disease Disease Progression Endothelial Cells Endothelium Environment Event Evolution Exposure to Functional disorder Gene Expression Grant Health Heart Diseases Heterogeneity Human Hypertension Immunofluorescence Immunologic In Vitro Inflammation Inflammatory Inflammatory Response Intercellular Junctions Lead Leukocytes Link Liquid substance Measurement Mechanics Methods Modeling Molecular Mus Organ Pathway interactions Pattern Permeability Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Protein Biochemistry Proteins Publishing RLK5-associated protein phosphatase Regulation Relative (related person)Reporting Research Research Personnel Resistance Role Signal Pathway Signal Transduction Simulate Stroke System Testing Time Transcriptional Regulation Vascular Diseases Vascular remodeling Veins Venous Video Microscopy Work athero susceptible atheroprotective base cadherin 5 capillary cell motility electric impedance hemodynamics improved in vitro activity in vivo innovation interest migration mouse model mutant new therapeutic target p21 activated kinase plakoglobin preconditioning protein complex protein distribution protein expression research study response shear stress trafficking

项目摘要

DESCRIPTION (provided by applicant): The hemodynamic environment appears to be a key regulator of endothelial cell phenotype throughout the circulation. This correlates to the development, localization and progression of atherosclerosis. We are testing this hypothesis with an innovative cell culture model that recreates human hemodynamic shear stress flow patterns from normal and disease regions within the circulation. Data from this work were the first to show that different shear stress patterns modulate the phenotype of the endothelium, including its inflammatory-state, arterial-venous identity, and characteristics of endothelial remodeling. In regions of atherosclerosis, blood flow forces (e.g., shear stress) are distinctly different from regions in arteries free from the disease. Likewise, the endothelium in atherosclerosis-susceptible regions possesses an inflammatory phenotype, higher rate of turnover and increased permeability. Thus, endothelial intercellular junctions might be compromised. There is a paradigm that junctions serve duel functions. The junctions not only serve a structural role in maintaining a permeability barrier, but also a signaling role, by regulating beta- and gamma catenin behavior. Although the structural role is established, the effect of shear stress on the signaling role is less understood and might contribute to differences in endothelial phenotype. Our overall objective is to define a mechanistic link between fluid shear stress and the functional consequences this has on junction stability and endothelial cell phenotype. Flow profiles from normal versus atherosclerosis-prone regions will be compared. Our specific aims are to investigate the effects of shear stress on changes in composition of VE-cadherin and PECAM junction complexes with the catenins. We will also investigate the functional consequences of that remodeling in terms of mechanotransduction, permeability and structural remodeling. Further, we will investigate the effect of shear stress on the signaling, trafficking and transcriptional activity of catenins. Once accomplished, these specific aims will improve understanding of the hemodynamic environment specifically as it relates to heart disease and stroke and lead to new therapeutic targets for this disease.

描述（由申请人提供）：血液动力学环境似乎是整个循环过程中内皮细胞表型的关键调节剂。这与动脉粥样硬化的发展，定位和进展有关。我们正在通过一种创新的细胞培养模型来检验这一假设，该模型从循环中正常和疾病区域重现人类血液动力学剪切应力流模式。这项工作的数据是第一个表明不同剪切应力模式调节内皮表型的数据，包括其炎症状态，动脉可能性身份和内皮重塑的特征。在动脉粥样硬化的地区，血流（例如，剪切应力）与无疾病的动脉区域明显不同。同样，动脉粥样硬化敏感区域中的内皮具有炎症表型，更高的周转率和增加的渗透率。因此，内皮内皮间连接可能会受到损害。有一个范式可以发挥决斗功能。连接不仅通过调节β-和伽马链球菌行为来维持渗透性屏障，而且发挥信号传导作用。尽管建立了结构作用，但剪切应力对信号传导作用的影响较少，并且可能导致内皮表型的差异。我们的总体目标是定义流体剪切应力与连接稳定性和内皮细胞表型的功能后果之间的机械联系。将比较来自正常和容易动脉粥样硬化区域的流量谱。我们的具体目的是研究剪切应力对与Catenins的VE-钙粘蛋白和PECAM结的组成变化的影响。我们还将根据机械转导，渗透性和结构重塑的重塑的功能后果。此外，我们将研究剪切应力对Catenin的信号传导，运输和转录活性的影响。一旦完成，这些具体目标将特别提高对血液动力学环境的理解，因为它与心脏病和中风有关，并为该疾病带来新的治疗靶标。