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：
7510666
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/7510666
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 Condition Cytoskeleton DNA Sequence Rearrangement Data Development Dextrans Disease Disruption 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 Protein Overexpression 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 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（所有）是由于肺泡毛细管屏障的丧失而导致的，具有高渗透性肺水肿和肺泡洪水。在ALI中，内皮细胞（EC）屏障功能的破坏（EC）屏障功能在ALI中至关重要，这会导致显着的发病率和死亡率。 HMGB1是败血症的晚期介质，在ALI的进化中发挥了作用，并且在败血症中是独一无二的，因为其水平比其他促炎细胞因子的水平更高，从而在临床上相关的时间范围内会干扰其影响。 HMGB1在ALI中的作用的机制尚不清楚。 PI是一种新生的医师科学家，已经产生了引人注目的初步数据，该数据支持以下假设：HMGB1信号传导对肌动蛋白细胞骨架会导致EC屏障破坏并有助于Ali病理生物学。该K08的具体目的是设计的：SA＃1。定义涉及HMGB1介导的EC屏障破坏的受体。 PI将利用人类肺EC和siRNA以及三种已知HMGB1受体的显性负面形式来定义所涉及的受体。 SA＃2。定义HMGB1受体结合后涉及信号转导的细胞信号分子。将利用分子和药理方法来定义与HMGB1介导的EC屏障破坏有关的信号传导机制。 SA＃3。用HSP27的突变体形式研究HMGB1磷酸化在HMGB1介导的EC屏障中介导的HSP27磷酸化的作用。体内研究将利用相关的敲除小鼠和体内siRNA。这些工具以及出色的指导将使PI实现此应用程序的目标。这些将阐明HMGB1破坏内皮细胞并为ALI做出贡献的机制，从而为这种毁灭性疾病提供了潜在的治疗干预的分子靶标。相关性：许多侮辱引起的急性肺损伤（ALI），最常见的是压倒性的全身感染（败血症）。败血症的一个介质HMGB1是独一无二的，因为它的水平升高到足以使医生干扰其行为，并且还参与了Ali的发展。该建议旨在定义HMGB1破坏肺内皮细胞屏障功能的机制，并有助于ALI，为将来的潜在治疗干预打开了大门。