Syndecan Interactions in Lung Injury and Repair

描述（由申请人提供）：本提案的中心目标是定义syndecan相互作用如何调节全身性炎症性疾病的肺损伤反应。对全身性炎症性疾病（如败血症）的肺损伤反应失调可导致急性肺损伤（ALI），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，并没有发展为急性呼吸窘迫综合征或更严重的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，减轻或逆转疾病进展，但潜在的生物学仍有待阐明。Syndecans由一个主要的细胞表面硫酸肝素蛋白聚糖（HSPGs）家族组成。Syndecans作为细胞表面的辅助受体，也作为细胞外环境中的可溶性热休克蛋白（HSPGs），因为它的外结构域可以在炎症条件下脱落。Syndecans通过其硫酸肝素（HS）链与配体结合，硫酸肝素是一种糖胺聚糖，可结合并调节几种与肺损伤有关的炎症介质。然而，syndecan相互作用在炎症性肺损伤中的确切作用尚未确定。当受到全身性炎症疾病（如内源性休克、革兰氏阳性中毒性休克或败血症）的动物模型时，Syndecan-1缺失小鼠显示出增加的肺损伤和死亡率。野生型小鼠肺部的Syndecan-1脱落是由全身炎症刺激引起的，抑制脱落会加重肺损伤，而纯化的Syndecan-1外结构域或HS可改善疾病参数。基于这些数据，本研究将探讨syndecan-1在一定程度上调节全身性炎症性疾病中高度复杂的肺损伤和修复机制的整体假设。目的1将定义syndecan-1如何促进肺部炎症的解决。目的2将确定syndecan-1如何减轻败血症患者的肺损伤和炎症。目的3将建立时间syndecan-1相互作用调节其在细胞表面的脱落。这些研究将明确晕厥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。

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.