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Endothelial focal adhesions in microvascular barrier dysfunction during ischemia-

缺血期间微血管屏障功能障碍中的内皮粘着斑

基本信息

批准号：
9276101
负责人：
MACK H WU
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276101
关键词：
Actinin Adherens Junction Adhesions Adhesives Antioxidants Basement membrane Binding Biochemical Biological Assay Brain hemorrhage Bypass CD47 gene Cell Adhesion Molecules Cell physiology Cell-Cell Adhesion Cells Cellular biology Clinical Complement Complex Cytoskeleton Development Disease Disseminated Malignant Neoplasm Dissociation Effectiveness Endothelial Cells Endothelium Evaluation Extracellular Matrix Extravasation Fibrinogen Focal Adhesion Kinase 1 Focal Adhesions Functional disorder Future Gene Mutation Gene Silencing Goals Hydrogen Peroxide Hypoxia Image Analysis Immune Impairment Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Integrin alpha5beta1 Integrins Intercellular Junctions Intestines Investigation Ischemia Knock-out Knowledge Leukocytes Liquid substance Maintenance Measurement Mediating Mesentery Microcirculation Microscopic Microvascular Dysfunction Microvascular Permeability Modality Molecular Mus Myocardial Infarction Nuclear Translocation Operative Surgical Procedures Organ Organ Transplantation Oxidants Oxidative Stress Pathway interactions Patients Peptides Permeability Pharmaceutical Preparations Pharmacology Physiological Plasma Play Plug-in Prevention Process Property Proteins Reaction Reactive Oxygen Species Regulation Reperfusion Injury Reperfusion Therapy Resuscitation Role Series Signal Transduction Stimulus Structure Superior mesenteric artery structure Talin Techniques Testing Therapeutic Therapeutic Effect Three-Dimensional Imaging Thrombosis Tissues Trauma Vinculin angiogenesis artery occlusion beta catenin clinical application comparative endothelial dysfunction experimental study in vivo injured innovation insight intravital microscopy knock-down knockout gene microvascular pathology mouse model neutrophil novel paxillin prevent public health relevance receptor release factor research and development response stem targeted treatment therapeutic evaluation venule

项目摘要

DESCRIPTION (provided by applicant): Ischemia/reperfusion (I/R) injury triggers a series of inflammatory responses in the microcirculation characterized by plasma leakage and leukocyte diapedesis. The microvascular pathology largely stems from endothelial barrier dysfunction, a complex cellular process that has not been fully understood at the molecular level. Emerging evidence indicates that the barrier property of the microvascular wall is controlled by dynamic interactions of endothelial cell-cell junctions and cell-matrix focal adhesions; the latter are maily composed of transmembrane integrin receptors and associated proteins such as kindlins and focal adhesion kinase (FAK). These molecules not only provide structural support for endothelial barrier integrity but also transmit biochemical signals that regulate barrier function. The goal of this project is to elucidate the molecular mechanisms underlying FAK-mediated microvascular hyperpermeability during I/R injury. We hypothesize that I/R-elicited oxidative stress upregulates FAK signaling in the microvascular endothelium, inducing integrin (α5β1, αvβ3) internalization and kindlin- targeted β-catenin nuclear translocation and junction dissociation, leading to weakened cell-matrix and cell-cell adhesions thereby impairing barrier integrity. This novel pathway will be tested in a series of mechanistic studies centered on intravital microscopic quantification of mesenteric microcirculation, leukocyte dynamics, and fluid/protein permeability in mice subjected to superior mesenteric artery occlusion followed by reperfusion. A newly developed mouse model of endothelial-specific conditional FAK knockout will be used in comparison with pharmacological inhibition of FAK. The in vivo studies will be complemented with imaging analyses and molecular assays in microvascular endothelial cells exposed to hypoxia/reoxygenation or oxidative stress. The studies will provide new mechanistic insights into I/R-induced microvascular injury contributing to the future development of targeted therapies to prevent tissue damage following resuscitation or reperfusion. Knowledge gained from this project may have broad implications in other diseases associated with microvascular barrier injury.

描述（由申请人提供）：缺血/再灌注（I/R）损伤引发微循环中的一系列炎症反应，其特征是血浆渗漏和白细胞渗出。微血管病理很大程度上源于内皮屏障功能障碍，这是一个在分子水平上尚未完全了解的复杂细胞过程。新的证据表明，微血管壁的屏障特性是由内皮细胞-细胞连接和细胞-基质粘着斑的动态相互作用控制的；后者主要由跨膜整合素受体和相关蛋白如kindlins和粘着斑激酶(FAK)组成。这些分子不仅为内皮屏障完整性提供结构支持，而且还传递调节屏障功能的生化信号。目标是该项目旨在阐明 I/R 损伤期间 FAK 介导的微血管通透性过高的分子机制。我们假设I/R引起的氧化应激上调微血管内皮中的FAK信号传导，诱导整合素（α5β1、αvβ3）内化和kindlin靶向β-连环蛋白核易位和连接解离，导致细胞-基质和细胞-细胞粘附减弱，从而损害屏障完整性。这一新途径将在一系列机制研究中进行测试，这些研究的重点是肠系膜上动脉闭塞再灌注小鼠的肠系膜微循环、白细胞动力学和液体/蛋白质渗透性的活体显微镜定量。新开发的内皮特异性条件性 FAK 敲除小鼠模型将用于与 FAK 的药理抑制进行比较。体内研究将与暴露于缺氧/复氧或氧化应激的微血管内皮细胞的成像分析和分子测定相补充。这些研究将为缺血再灌注引起的微血管损伤提供新的机制见解，有助于未来开发预防复苏或再灌注后组织损伤的靶向疗法。从该项目中获得的知识可能对与微血管屏障损伤相关的其他疾病具有广泛的影响。