Integrin Beta 4 in Vascular Inflammatory Responses

整合素 Beta 4 在血管炎症反应中的作用

基本信息

批准号：
8320072
负责人：
JEFFREY R JACOBSON
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：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320072
关键词：
3&apos Untranslated Regions Acute Animal Model Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Biological Preservation Blood Vessels C-terminal Cell Nucleus Cell membrane Cholesterol Clinical Cytoplasmic Tail Cytoskeletal Proteins Data Endothelial Cells Engineering Enhancers Extracellular Matrix Extracellular Matrix Proteins F-Actin Focal Adhesions Gene Expression Genetic Polymorphism Genomics Human Hydroxymethylglutaryl-CoA Reductase Inhibitors IL8 gene ITGB4 gene Inflammation Mediators Inflammatory Inflammatory Response Integrin Inhibition Integrin beta4 Integrins Intensive Care Units Interleukin-6 Laminin Laminin Receptor Lipopolysaccharides Luciferases Lung Lung Inflammation MAP Kinase Gene Mediating Modeling Morbidity - disease rate Mus PTK2 gene Patients Permeability Pharmaceutical Preparations Physicians Predisposition Protective Agents Proteins Regulation Regulatory Element Reporter Research Research Design Research Personnel Role Scientist Serum Signal Pathway Signal Transduction Simvastatin Single Nucleotide Polymorphism Small Interfering RNA Talin Tyrosine Phosphorylation Up-Regulation Vascular Permeabilities Ventilator Ventilator-induced lung injury Vinculin attenuation cell type cytokine design in vivo lung injury monolayer mortality multidisciplinary mutant neutralizing antibody new therapeutic target novel paxillin plectin promoter protective effect protein expression public health relevance receptor response therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. A cardinal feature of ALI is an increase in lung vascular permeability, often precipitated by an exuberant inflammatory response with subsequent endothelial barrier disruption. Strategies designed to attenuate vascular permeability could provide attractive novel therapeutic targets and approaches. We previously identified the protective effects of simvastatin, an HMG CoA-reductase inhibitor, in a murine model of ALI and defined potent anti-inflammatory effects of statins including augmentation of endothelial cell (EC) barrier function. Genomic studies of simvastatin-mediated EC gene expression identified the dramatic upregulation of integrin ¿4, a laminin receptor expressed in numerous cell types including EC, suggesting a potentially novel ALI target. While information is limited as to the role of integrin ¿4 in EC, integrins are known to serve as mediators of inflammatory signaling and we have recently confirmed the attenuation of lung inflammation associated with the inhibition of integrin ¿4 in separate models of murine ALI and ventilator-induced lung injury (VILI). Accordingly, we now hypothesize that integrin ¿4 mediates EC inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting. PUBLIC HEALTH RELEVANCE: Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. Although treatment options for ALI are severely limited we previously identified the protective effects of simvastatin, a drug commonly used to lower serum cholesterol levels, in an animal model of ALI and our subsequent genomic studies identified the dramatic increase in the protein integrin ¿4 in response to simvastatin treatment. Accordingly, we now hypothesize that integrin ¿4 mediates vascular inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting.

描述（由适用提供）：急性炎症性肺损伤（ALI）是一个挑战临床问题，在重症监护病房通常遇到，并且与显着的发病率和死亡率有关。 ALI的基本特征是肺血管通透性的增加，通常由炎症的炎症反应引起，随后发生内皮屏障破坏。旨在减弱血管通透性的策略可以提供有吸引力的新型治疗靶标和方法。我们先前在ALI的鼠模型中识别了辛伐他汀（HMG CoA还原酶抑制剂）的受保护作用，并确定了他汀类药物的有效抗炎作用，包括增强内皮细胞（EC）屏障功能。辛伐他汀介导的EC基因表达的基因组研究确定了整联蛋白的戏剧性上调€4，这是一种在包括EC在内的许多细胞类型中表达的层粘连蛋白受体，这表明潜在的新型ALI靶标。尽管对整合素„ 4在EC中的作用的信息受到限制，但已知整联蛋白是炎症信号传导的介体，我们最近证实了与抑制整合素的肺部感染的衰减，在鼠ALI和呼吸机诱导的肺部诱导的肺损伤（VILI）中抑制了4。据此，我们现在假设整联蛋白»4介导了ALI中的EC炎症反应，并且可以在这种情况下作为高度新颖的治疗靶点。公共卫生相关性：急性炎症性肺损伤（ALI）是一个挑战临床问题，在重症监护病房通常遇到，并且与大量发病率和死亡率有关。尽管ALI的治疗方案受到严重限制，但我们先前鉴定出辛伐他汀的保护作用，辛伐他汀（一种通常用于降低血清胆固醇水平的药物，在ALI的动物模型中，我们随后的基因组研究确定了蛋白质整合蛋白的急剧增加，以响应于辛伐他汀治疗。根据，我们现在假设整联蛋白4介导了ALI中的血管炎症反应，并且在这种情况下可能是高度新颖的治疗靶标。