Role Of p120 Catenin In Sepsis-Induced Lung Injury

p120 连环蛋白在脓毒症引起的肺损伤中的作用

基本信息

批准号：
8266350
负责人：
Guochang Hu
金额：
$ 38.86万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266350
关键词：
Acute Lung Injury Address Adherens Junction Adhesions Alveolar Alveolus Anti-Inflammatory Agents Anti-inflammatory Bacterial Infections Binding Blood Vessels Breathing Calpain Cell Adhesion Molecules Cells Complement Factor B Complementary DNA Data Depressed mood Development Down-Regulation Edema Elements Endothelial Cells Endothelium Endotoxins Epithelial Event Exhibits Gene Deletion Gene Targeting Hospitals Immune response Inflammation Inflammatory Inflammatory Response Injury Intensive Care Units Intercellular adhesion molecule 1 Life Lipopolysaccharides Liposomes Lung Lung Inflammation Mechanics Mediating Membrane Mitogen-Activated Protein Kinases Modeling Molecular Molecular Genetics Multiple Organ Failure Mus Mutant Strains Mice NADPH Oxidase NF-kappa B Neutrophil Infiltration Nuclear Oxidants Participant Pathogenesis Pathway interactions Play Pneumonia Prevention Production Proteins Regulation Relative (related person)Research Role Sepsis Septic Shock Severities Signal Pathway Signal Transduction Small Interfering RNA Supportive care Testing Therapeutic Transgenic Mice Transgenic Organisms Up-Regulation Vascular Endothelium cell injury cytokine design in vivo inhibitor/antagonist interest lung injury lung vascular injury migration monolayer mutant neutrophil novel overexpression prevent protein expression public health relevance research study response toll-like receptor 4 trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The bacterial endotoxin (lipopolysaccharide, LPS) can trigger systemic hyper-inflammatory response that subsequently leads to multiple organ dysfunction syndrome. LPS binding to toll-like receptor 4 (TLR4) induces the activation of mitogen-activated protein kinase (MAPK) and nuclear factor (B (NF-(B) resulting in production of pro-inflammatory cytokines. When this production becomes uncontrolled and excessive, it leads to the development of septic shock. p120-catenin, a component of adherens junctions in endothelial cells and other polarized adherent cells, has recently been implicated in the intrinsic regulation of inflammation. p120-catenin null epidermal cells exhibited increased activity of NF-(B and proinflammatory NF-(B targets. In preliminary experiments, we made the intriguing observation that deletion of p120 in the lung vasculature with specific siRNA rendered the mice highly susceptible to LPS, suggesting that p120 is a crucial element of the host response to sepsis. Our supporting data further demonstrate that p120-catenin expression in the mouse lung is rapidly reduced after LPS challenge. Also, deletion of p120-catenin in pulmonary vasculature endothelium and cultured pulmonary microvascular endothelial cells significantly increased LPS-induced expression of intercellular adhesion molecule-1 (ICAM-1), neutrophil adhesion, and transendothelial neutrophil migration via activation of NF-(B and MAPK signaling. Collectively, these data suggest that p120-catenin serves to dampen the LPS-induced inflammatory response in lungs. The objectives of the proposed studies are to define the anti-inflammatory role of p120-catenin, determine the mechanism of p120-catenin degradation induced by LPS, and to explore the possibility that p120-catenin interferes with the TLR4-activated signaling pathway to mitigate lung inflammatory injury. The proposal will address the following Specific Aims: 1. To determine the mechanisms of regulation of pulmonary endothelial p120-catenin expression in response to LPS-induced lung injury. Here we will dissect the signaling pathways that cause the loss of p120 in the pulmonary microvasculature following LPS challenge. 2. To define the role of endothelial p120-catenin expression in the regulation of LPS-induced lung inflammatory injury. 3. To identify the signaling pathways by which endothelial p120 regulates TLR4 signaling-mediated lung inflammation. The identification of p120-catenin-activated pathways modulating LPS-induced sepsis will be of great interest in the design of therapeutic strategies for the treatment or prevention of acute lung injury. PUBLIC HEALTH RELEVANCE: Acute lung injury caused by widespread bacterial infection is a severe and life threatening condition that requires a mechanical breathing machine and other supportive care in hospital intensive care units. We have shown that protein p120-catenin in the lung plays an essential role in preventing severe lung inflammation that causes acute lung injury. The purpose of this research is to define the basic molecular mechanisms by which p120-catenin regulates lung inflammation in order to design new and effective strategies for the treatment or prevention of acute lung injury.

描述（由申请人提供）：细菌内毒素（脂多糖，LPS）可以触发全身性高炎反应，随后导致多个器官功能障碍综合征。 LPS与Toll样受体4（TLR4）结合诱导有丝分裂原激活的蛋白激酶（MAPK）和核因子的激活（B（NF-（b），导致促炎性细胞因子的产生。，它导致败血性休克的发展。 - （B和促炎性NF-（B靶。在初步实验中，我们进行了一个有趣的观察结果，即在肺脉管系统中删除P120，具有特定的siRNA使小鼠对LPS高度敏感，这表明P120是宿主响应响应的重要元素败血症的数据进一步证明了小鼠肺中的P120-catenin表达在LPS挑战之后迅速降低，肺部静脉内皮细胞中P120-catenin的删除通过激活NF-（B和MAPK信号传导），分子1（ICAM-1），中性粒细胞粘附和跨内皮中性粒细胞迁移。总的来说，这些数据表明P120-Catenin可抑制LPS诱导的肺部炎症反应。拟议的研究的目标是定义P120-catenin的抗炎作用，确定LPS诱导的P120-catenin降解的机制，并探索P120-Catenin会干扰TLR4激活的信号传导途径的可能性肺部炎症损伤。该提案将解决以下特定目的：1。确定响应LPS诱导的肺损伤的肺内皮P120-catenin表达的调节机制。在这里，我们将剖析在LPS挑战后肺微脉管系统中导致P120损失的信号通路。 2。定义内皮P120-catenin表达在LPS诱导的肺炎症性损伤调节中的作用。 3。确定内皮P120调节TLR4信号介导的肺部炎症的信号传导途径。调节LPS引起的败血症的P120-Catenin激活途径的鉴定将在设计或预防急性肺损伤的治疗策略中引起极大的兴趣。公共卫生相关性：广泛的细菌感染引起的急性肺损伤是一种严重且威胁生命的疾病，需要机械呼吸机和其他医院重症监护病房的其他支持护理。我们已经表明，肺中的蛋白p120-catenin在防止导致急性肺损伤的严重肺部炎症中起着至关重要的作用。这项研究的目的是定义p120-catenin调节肺部炎症的基本分子机制，以设计新的有效策略，以治疗或预防急性肺损伤。