Syndecan Interactions in Lung Injury and Repair

Syndecan 在肺损伤和修复中的相互作用

基本信息

批准号：
8086196
负责人：
Pyong Woo Park
金额：
$ 43.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2011-05-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8086196
关键词：
Acute Acute Lung Injury Adult Respiratory Distress Syndrome Animal Model Applications Grants Attenuated Binding Biology CXCL1 gene Cell surface Complex Data Development Disease Disease Progression Endogenous Factors Endotoxic Shock Environment Epithelial Failure Family Foundations Functional disorder Glycosaminoglycans Goals Healed Heparan Sulfate Proteoglycan Heparitin Sulfate Host Defense Mechanism Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Knockout Mice Lead Ligand Binding Ligands Ligation Lung Lung Inflammation Lung diseases Metalloproteases Modification Molecular Molecular Target Morbidity - disease rate Mus Neutrophil Infiltration Patients Phase Puncture procedure Resolution Role Sepsis Source T-Lymphocyte Testing Therapeutic TimeLine Tissues Toxic Shock Syndrome Wild Type Mouse attenuation base design extracellular healing improved injury and repair killings lung injury mortality novel therapeutic intervention response to injury septic syndecan

项目摘要

DESCRIPTION (provided by applicant): The central goal of this proposal is to define how syndecan interactions modulate lung injury responses in systemic inflammatory diseases. Dysregulated lung injury responses to systemic inflammatory diseases, such as sepsis, can lead to acute lung injury (ALI) and are a major cause of morbidity and mortality. However, many patients survive the initial phase of lung injury and do not progress to ALI or to the more severe form of ALI, acute respiratory distress syndrome (ARDS). These data suggest the importance of endogenous protective mechanisms that attenuate or reverse disease progression, but the underlying biology remains to be elucidated. Syndecans comprise a major family of cell surface heparan sulfate proteoglycans (HSPGs). Syndecans function as coreceptors on the cell surface and also as soluble HSPGs in the extracelular environment because its ectodomain can be shed under inflammatory conditions. Syndecans bind to ligands through its heparan sulfate (HS) chains, a glycosaminoglycan that binds to and regulates several inflammatory mediators implicated in lung injury. However, the precise role of syndecan interactions in inflammatory lung injury has yet to be determined. Syndecan-1 null mice show increased lung injury and mortality when subjected to animal models of systemic inflammatory diseases, such as endotoxic shock, Gram-positive toxic shock, or sepsis. Syndecan-1 shedding is induced in the lungs of wild type mice by the systemic inflammatory challenge, and inhibition of shedding exacerbates lung injury, whereas administration of purified syndecan-1 ectodomain or HS improves disease parameters. Based on these data, this proposal will examine the overall hypothesis that syndecan-1 modulates, in part, the highly complex mechanisms of lung injury and repair in systemic inflammatory diseases in 3 Specific Aims. Aim 1 wil define how syndecan-1 facilitates the resolution of lung inflammation. Aim 2 will determine how syndecan-1 attenuates lung injury and inflammation in sepsis. Aim 3 will establish that temporal syndecan-1 interactions regulate its shedding at the cell surface. These studies should define the key functions of syndecans in lung injury and repair, and provide a mechanistic foundation for the design and development of new therapeutic approaches against inflammatory lung diseases. PUBLIC HEALTH RELEVANCE: Correctly coordinated inflammation protects from infection and helps heal tissues. However, excessive and inappropriate inflammation can damage tissues and lead to serious complications associated with high morbidity and mortality, such as lung injury, dysfunction, and failure. This grant application will investigate how one of our own molecules called syndecan corrects the dysregulated inflammatory response in the lung, with the goal of identifying new molecular targets for the effective therapeutic control of inflammatory lung diseases.

描述（由申请人提供）：该提案的中心目标是确定多聚糖相互作用如何调节全身炎症性疾病中的肺损伤反应。对全身炎症性疾病（例如败血症）的肺损伤反应失调可导致急性肺损伤（ALI），并且是发病和死亡的主要原因。然而，许多患者在肺损伤的初始阶段幸存下来，并且没有进展为 ALI 或更严重的 ALI，即急性呼吸窘迫综合征 (ARDS)。这些数据表明内源性保护机制对于减弱或逆转疾病进展的重要性，但其潜在的生物学机制仍有待阐明。 Syndecans 是细胞表面硫酸乙酰肝素蛋白聚糖 (HSPG) 的主要家族。多配体在细胞表面充当辅助受体，并且在细胞外环境中充当可溶性 HSPG，因为其胞外域可以在炎症条件下脱落。多配体通过其硫酸乙酰肝素 (HS) 链与配体结合，硫酸乙酰肝素是一种糖胺聚糖，可结合并调节与肺损伤有关的几种炎症介质。然而，多聚糖相互作用在炎症性肺损伤中的确切作用尚未确定。 Syndecan-1缺失小鼠在接受系统性炎症疾病（例如内毒素休克、革兰氏阳性中毒性休克或败血症）的动物模型时表现出肺损伤和死亡率增加。野生型小鼠肺部的 Syndecan-1 脱落是由全身炎症引起的，抑制脱落会加剧肺损伤，而纯化的 syndecan-1 胞外域或 HS 的给药可改善疾病参数。基于这些数据，该提案将在 3 个具体目标中检验 syndecan-1 在一定程度上调节全身炎症性疾病中肺损伤和修复的高度复杂机制的总体假设。目标 1 将定义 syndecan-1 如何促进肺部炎症的解决。目标 2 将确定 syndecan-1 如何减轻脓毒症中的肺损伤和炎症。目标 3 将确定 Syndecan-1 的时间相互作用调节其在细胞表面的脱落。这些研究应明确多配体在肺损伤和修复中的关键功能，并为设计和开发针对炎症性肺部疾病的新治疗方法提供机制基础。公共卫生相关性：正确协调的炎症可以防止感染并有助于组织愈合。然而，过度和不适当的炎症会损害组织并导致与高发病率和死亡率相关的严重并发症，例如肺损伤、功能障碍和衰竭。这项拨款申请将研究我们自己的一种名为多配体聚糖的分子如何纠正肺部失调的炎症反应，目的是确定有效治疗控制炎症性肺部疾病的新分子靶点。