Syndecan Interactions in Lung Injury and Repair

描述(由申请人提供)：该提案的中心目标是定义Syndecan相互作用如何调节全身炎症性疾病中的肺损伤反应。肺损伤对全身炎症性疾病(如脓毒症)的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期存活下来，没有发展到ALI或更严重的ALI形式，即急性呼吸窘迫综合征(ARDS)。这些数据表明了抑制或逆转疾病进展的内源性保护机制的重要性，但其潜在的生物学基础仍有待阐明。Syndecans是细胞表面硫酸乙酰肝素蛋白多糖(HSPGs)的一个重要家族。Syndecans在细胞表面作为辅助受体发挥作用，在细胞外环境中也作为可溶性HSPGs发挥作用，因为它的胞外结构域在炎症条件下可以脱落。Syndecans通过其硫酸乙酰肝素链(HS)与配体结合，这是一种糖胺多糖，可以结合并调节几种与肺损伤有关的炎症介质。然而，Syndecan相互作用在炎性肺损伤中的确切作用尚未确定。Syndecan-1基因缺失的小鼠在受到内毒素休克、革兰氏阳性中毒性休克或脓毒症等全身炎症性疾病动物模型的影响时，肺损伤和死亡率增加。全身炎症刺激可诱导野生型小鼠肺内Syndecan-1脱落，抑制Syndecan-1脱落可加重肺损伤，而给予纯化的Syndecan-1胞外区或HS可改善疾病参数。基于这些数据，这项建议将检验Syndecan-1部分地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三个特定目标的总体假设。目的1明确Syndecan-1如何促进肺部炎症的消退。目的2将确定Syndecan-1如何减轻脓毒症时的肺损伤和炎症。目标3将建立时间上的syndecan-1相互作用调节其在细胞表面的脱落。这些研究将明确Syndecans在肺损伤和修复中的关键功能，并为设计和开发抗炎症性肺部疾病的新治疗方法提供机制基础。 与公共卫生相关：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，如肺损伤、功能障碍和衰竭。这项拨款申请将调查我们自己的一种名为Syndecan的分子如何纠正肺内失调的炎症反应，目标是确定有效治疗炎症性肺部疾病的新分子靶点。

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.