The Role of HMGB1 in Acute Lung Injury-Induced Endothelial Cell Permeability

HMGB1 在急性肺损伤诱导的内皮细胞通透性中的作用

基本信息

批准号：
7682958
负责人：
RACHEL K WOLFSON
金额：
$ 12.44万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682958
关键词：
Actin-Binding Protein Actins Acute Acute Lung Injury Address Adhesives Adult Respiratory Distress Syndrome Advanced Glycosylation End Products Alveolar Animal Model Binding Biological Assay Blood Vessels Blood capillaries Bronchoalveolar Lavage Fluid Bundling Cell Adhesion Molecules Cell Shape Cells Cellular Stress Cytoskeleton DNA Sequence Rearrangement Data Development Dextrans Disease Dominant-Negative Mutation Electrical Resistance Endothelial Cells Endothelium Endotoxemia Event Evolution Extracellular Signal Regulated Kinases Floods Functional disorder Future Genes Genetic Transcription Goals HMGB1 gene Heat Shock Protein 27 Heat shock proteins Heat-Shock Response Human IRAK1 gene Immunofluorescence Immunologic In Vitro Inflammatory Intercellular adhesion molecule 1 Knockout Mice Lead Ligation Link Lipopolysaccharides Liquid substance Lung MAP-kinase-activated kinase 2 MAPK14 gene MAPKAP kinase-2 Maintenance Mechanical Stress Mediating Mediator of activation protein Mentorship Methods Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Molecular Chaperones Molecular Target Morbidity - disease rate Movement Mus Nuclear Pathway interactions Patients Permeability Phosphorylation Physicians Play Post-Translational Protein Processing Process Property Protein Kinase Proteins Pulmonary Edema Regulation Reperfusion Injury Research Personnel Role Scientist Secondary to Sepsis Sepsis Syndrome Septic Shock Series Serum Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Small Interfering RNA Stimulus Stress Stretching System Systemic infection TLR4 gene Testing Therapeutic Intervention Time Toll-Like Receptor 2 Vascular Cell Adhesion Molecule-1 capillary cell injury clinically relevant cytokine design dextran extracellular human MAPK14 protein in vivo inhibitor/antagonist lung injury monocyte mortality mutant neutrophil overexpression polymerization preconditioning prevent programs receptor receptor binding research study solute stress-activated protein kinase 1 tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (All) results from loss of the alveolar-capillary barrier with high-permeability pulmonary edema and alveolar flooding. Disruption of endothelial cell (EC) barrier function secondary to paracellular gap formation and cytoskeleton changes is critical in ALI, which causes significant morbidity and mortality. HMGB1, a late mediator of sepsis, plays a role in the evolution of ALI and is unique in sepsis as its levels rise later than those of other proinflammatory cytokines, offering the potential to interfere with its effects in a clinically relevant time frame. The mechanism of HMGB1 's role in ALI is unknown. The PI, a nascent physician-scientist, has generated compelling preliminary data which support the hypothesis that HMGB1 signaling to the actin cytoskeleton results in EC barrier disruption and contributes to ALI pathobiology. The Specific Aims of this K08 are designed: SA#1. To define the receptor involved in HMGB1 -mediated EC barrier disruption. The PI will utilize human lung EC and siRNA and dominant negative forms of three known HMGB1 receptors to define the receptor(s) involved. SA#2. To define the cell signaling molecules involved in signal transduction after HMGB1-receptor binding. Molecular and pharmacologic approaches will be utilized to define the signaling mechanisms involved in HMGB1-mediated EC barrier disruption. SA#3. To define cross-talk between HMGB1 and heat shock protein (Hsp) 27, which stabilizes the actin cytoskeleton in EC to maintain cell shape, using mutant forms of Hsp27 to study the role of Hsp27 phosphorylation in HMGB1 - mediated EC barrier disruption. In vivo studies will utilize relevant knockout mice and in vivo siRNA. These tools along with excellent mentorship will allow the PI to achieve the goals of this application. These will elucidate the mechanism by which HMGB1 disrupts endothelial cells and contributes to ALI, providing a molecular target for potential therapeutic intervention in this devastating disorder. Relevance: Acute lung injury (ALI) results from many insults, one of the most common being overwhelming systemic infection (sepsis). One mediator of sepsis, HMGB1, is unique because its levels rise late enough for physicians to interfere with its actions, and is also involved in the development of ALI. This proposal aims to define the mechanism by which HMGB1 disrupts lung endothelial cell barrier function and contributes to ALI, opening the door for potential therapeutic intervention in the future.

描述（由申请人提供）：急性肺损伤（全部）是由于肺泡毛细血管屏障丧失并伴有高渗透性肺水肿和肺泡充盈所致。细胞旁间隙形成和细胞骨架变化继发的内皮细胞 (EC) 屏障功能破坏对于 ALI 至关重要，会导致严重的发病率和死亡率。 HMGB1 是脓毒症的晚期介质，在 ALI 的演变中发挥着重要作用，并且在脓毒症中具有独特性，因为其水平上升晚于其他促炎细胞因子，因此有可能在临床相关时间范围内干扰其作用。 HMGB1 在 ALI 中的作用机制尚不清楚。作为一名新兴的医师科学家，PI 已经生成了令人信服的初步数据，这些数据支持以下假设：向肌动蛋白细胞骨架发出 HMGB1 信号会导致 EC 屏障破坏并导致 ALI 病理学。 K08 的具体目标是：SA#1。定义参与 HMGB1 介导的 EC 屏障破坏的受体。 PI 将利用人肺 EC 和 siRNA 以及三种已知 HMGB1 受体的显性失活形式来定义所涉及的受体。 SA#2。定义 HMGB1 受体结合后参与信号转导的细胞信号分子。将利用分子和药理学方法来定义 HMGB1 介导的 EC 屏障破坏所涉及的信号传导机制。 SA#3。为了定义 HMGB1 和热休克蛋白 (Hsp) 27 之间的串扰（稳定 EC 中的肌动蛋白细胞骨架以维持细胞形状），使用 Hsp27 的突变形式来研究 Hsp27 磷酸化在 HMGB1 介导的 EC 屏障破坏中的作用。体内研究将利用相关的基因敲除小鼠和体内 siRNA。这些工具加上出色的指导将使 PI 能够实现此应用程序的目标。这些将阐明 HMGB1 破坏内皮细胞并导致 ALI 的机制，为这种破坏性疾病的潜在治疗干预提供分子靶点。相关性：急性肺损伤 (ALI) 由多种损伤引起，其中最常见的一种是压倒性全身感染（脓毒症）。脓毒症的一种介质 HMGB1 是独一无二的，因为它的水平上升得晚，足以让医生干扰其作用，并且还参与了 ALI 的发展。该提案旨在明确 HMGB1 破坏肺内皮细胞屏障功能并导致 ALI 的机制，为未来潜在的治疗干预打开大门。