Syndecan Interactions in Lung Injury and Repair

Syndecan 在肺损伤和修复中的相互作用

• 批准号: 8259421
• 负责人: Pyong Woo Park
• 金额: $ 43.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/8259421
• 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; Grant; 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; killings; lung injury; lung repair; mortality; novel therapeutic intervention; public health relevance; response to injury; septic; syndecan

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）：本提案的中心目标是确定多配体蛋白聚糖相互作用如何调节全身性炎症性疾病中的肺损伤反应。对全身性炎性疾病（如脓毒症）的失调的肺损伤反应可导致急性肺损伤（ALI），并且是发病率和死亡率的主要原因。然而，许多患者在肺损伤的初始阶段存活下来，并且没有进展为ALI或更严重形式的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的重要性，减轻或逆转疾病的进展，但潜在的生物学仍有待阐明。多配体蛋白聚糖是细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）的主要家族。多配体蛋白聚糖作为细胞表面上的辅助受体发挥作用，并且还作为细胞外环境中的可溶性HSPG发挥作用，因为其胞外域可以在炎症条件下脱落。多配体聚糖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，syndecan相互作用在炎症性肺损伤中的确切作用尚未确定。当经受全身性炎性疾病的动物模型（例如内毒素休克、革兰氏阳性中毒性休克或脓毒症）时，Syndecan-1缺失小鼠显示增加的肺损伤和死亡率。在野生型小鼠的肺中通过全身性炎症激发诱导多配体蛋白聚糖-1脱落，并且抑制脱落加剧肺损伤，而施用纯化的多配体蛋白聚糖-1胞外域或HS改善疾病参数。基于这些数据，本提案将在3个特定目标中检验syndecan-1部分调节系统性炎症性疾病中肺损伤和修复的高度复杂机制的总体假设。目的1将明确syndecan-1如何促进肺部炎症的消退。目的2将确定syndecan-1如何减轻脓毒症中的肺损伤和炎症。目的3将确定时间syndecan-1相互作用调节其在细胞表面的脱落。这些研究应该确定syndecans在肺损伤和修复中的关键功能，并为设计和开发新的治疗方法提供机制基础。 公共卫生相关性：正确协调的炎症保护免受感染，并有助于愈合组织。然而，过度和不适当的炎症可损伤组织并导致与高发病率和死亡率相关的严重并发症，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称为syndecan的分子如何纠正肺部失调的炎症反应，目的是确定新的分子靶点，以有效治疗控制炎症性肺部疾病。