Hepatocyte Growth Factor/c-Met Invovement in Lung EC Barrier Regulation

肝细胞生长因子/c-Met 参与肺 EC 屏障调节

基本信息

批准号：
8214992
负责人：
Ravi Salgia
金额：
$ 30.06万
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：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214992
关键词：
Actins Acute Lung Injury Animal Model Architecture Arteriosclerosis Atomic Force Microscopy Attenuated Binding Blood Vessels Bronchoalveolar Lavage CD44 Antigens CD44 gene Cell Surface Receptors Cell membrane Cells Code Critical Illness Cytoskeleton DNA Sequence Rearrangement Data Defect Disease Dynamin 2 Edema Endothelial Cells Extravasation Genes Glycoproteins Growth Factor Guanine Nucleotide Exchange Factors Hepatocyte Growth Factor Heterozygote Human Hyaluronan Immunofluorescence Immunologic Immunohistochemistry In Vitro Inflammation Inflammatory Knockout Mice Lead Life Lipopolysaccharides Liquid substance Lung Mediating Membrane Microdomains Modeling Morbidity - disease rate Mus Myosin Light Chain Kinase Patients Permeability Polymorphism Analysis Predisposition Process Production Property Protein Tyrosine Kinase Proteins Proteomics Publishing Pulmonary Edema Regulation Research Role Series Signal Transduction Signal Transduction Pathway Single Nucleotide Polymorphism Small Interfering RNA Sphingosine-1-Phosphate Receptor Structure System Techniques Testing Therapeutic Tissues Transactivation Vascular Permeabilities Vesicle X-Ray Computed Tomography angiogenesis caveolin 1 cellular imaging cytokine design genetic regulatory protein in vivo induced pluripotent stem cell lung injury meetings mortality novel paxillin receptor restoration

项目摘要

An alteration in vascular permeability is a defining feature of diverse processes including arteriosclerosis, inflammation, acute lung injury (ALI) and angiogenesis. In contrast, there is little known about processes that determine barrier protection or barrier restoration after edemagenic agents. We have previously shown that hepatocyte growth factor (HGF) binding to its cell surface receptor tyrosine kinase, c-Met, promotes increased EC barrier function via cytoskeletal rearrangement and attenuates inflammatory lung edema formation. Our data indicate that HGF promotes c-Met recruitment into specialized caveolin-1-enriched plasma membrane microdomains known as lipid rafts and transactivates sphingosine 1-phosphate receptor (S1P1) and CD44 (a major hyaluronan glycoprotein receptor) within these lipid raft structures. We have identified several potential regulators of HGF/c-Met-induced actin cytoskeletal rearrangement and consequent EC barrier enhancement in lipid rafts including the Rac1 exchange factor, Tiaml, the vesicle regulatory protein, dynamin 2, myosin light chain kinase (MLCK) and paxillin. Further, genes encoding c-Met and paxillin contain coding single nucleotide polymorphisms (SNPs) which potentially alter function and lead to increased susceptibility to ALI. Specific Aim #1 will identify the role of these SNPs in HGF/c-Met signaling from lipid rafts to the actin cytoskeleton and consequent human EC barrier regulation. Our preliminary data in murine model of lipopolysaccharide (LPS)-induced pulmonary vascular hyper-permeability suggests that caveolin-1 regulates HGF-mediated vascular integrity in vivo. Specific Aim #2 will define HGF/c-Met/caveolin-1 interactions in the regulation of endothelial cortical actin formation, tension and lung permeability. Further, our published data indicates that HGF/c-Met transactivation of the S1P1 is crucial for its EC barrierenhancing properties. Thus, to explore growth factor transactivation in regulating EC barrier function, Specific Aim #3 will identify HGF/c-Met/S1P1 interactions in the regulation of endothelial cortical actin formation, tension and lung permeability. Specific Aim #4 will define HGF/c-Met/CD44 interactions in the regulation of endothelial cortical actin formation, tension and lung permeability. Increased understanding of HGF/c-Met-mediated signal transduction and EC barrier regulation from lipid rafts may provide novel therapies for a variety of disease processes involving defects in EC barrier regulation.

血管通透性的改变是多种过程的一个决定性特征，包括动脉硬化、炎症、急性肺损伤（ALI）和血管生成。相比之下，人们对以下过程知之甚少：确定使用致水肿剂后的屏障保护或屏障恢复。我们之前已经证明了肝细胞生长因子 (HGF) 与其细胞表面受体酪氨酸激酶 c-Met 结合，促进肝细胞生长因子 (HGF) 的增加 EC 通过细胞骨架重排发挥屏障功能，并减轻炎性肺水肿的形成。我们的数据表明 HGF 促进 c-Met 募集到专门的富含 Caveolin-1 的血浆中称为脂筏的膜微结构域可反式激活 1-磷酸鞘氨醇受体 (S1P1) 这些脂筏结构中存在 CD44（一种主要的透明质酸糖蛋白受体）。我们已经确定 HGF/c-Met 诱导的肌动蛋白细胞骨架重排和随后的 EC 的几个潜在调节因子脂筏屏障增强，包括 Rac1 交换因子、Tiaml、囊泡调节蛋白、动力 2、肌球蛋白轻链激酶 (MLCK) 和桩蛋白。此外，编码c-Met和桩蛋白的基因含有编码单核苷酸多态性 (SNP)，可能会改变功能并导致增加对 ALI 的易感性。具体目标 #1 将确定这些 SNP 在脂质 HGF/c-Met 信号传导中的作用筏到肌动蛋白细胞骨架和随后的人类 EC 屏障调节。我们在小鼠身上的初步数据脂多糖 (LPS) 诱导的肺血管通透性过高模型表明，caveolin-1 调节 HGF 介导的体内血管完整性。具体目标 #2 将定义 HGF/c-Met/caveolin-1 内皮皮质肌动蛋白形成、张力和肺通透性调节中的相互作用。更远，我们发表的数据表明 S1P1 的 HGF/c-Met 反式激活对其 EC 屏障增强至关重要特性。因此，为了探索生长因子反式激活在调节 EC 屏障功能中的作用，具体目标 #3 将确定 HGF/c-Met/S1P1 在内皮皮质肌动蛋白调节中的相互作用形成、张力和肺通透性。具体目标 #4 将定义 HGF/c-Met/CD44 相互作用内皮皮质肌动蛋白形成、张力和肺通透性的调节。增加了解 HGF/c-Met 介导的信号转导和脂筏的 EC 屏障调节可能提供新的针对涉及 EC 屏障调节缺陷的多种疾病过程的疗法。