Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis

总结 该项目的目的是解决整个项目的中心假设，即蛋白质糖基化和 糖蛋白重塑调节脓毒症的凝血病和炎症。该研究项目将 研究硫酸乙酰肝素（HS）、硫酸乙酰肝素蛋白聚糖（HSPG）和基质的作用 金属蛋白酶（MMPs）在凝血障碍和脓毒症炎症中的作用。这项研究吸引了所有 该计划的核心设施，并利用项目领导人和核心的综合专业知识 感染和败血症、炎症生物学、凝血、凝血病、蛋白质组学和糖生物学领域的领导者。 从最近的文献和初步数据来看，HS附着于内皮HSPGs改变了脓毒症的结局 与MMP诱导的HSPG从血管内皮细胞脱落一致。此外，血管HS 缺乏对由不同微生物病原体引起的脓毒症的结果具有相反的影响， 革兰氏阳性肺炎链球菌（SPN）和革兰氏阴性肠道鼠伤寒沙门氏菌（ST）。 此外，MMP抑制影响HSPG脱落，并在脓毒症的发病机制中提供保护作用 这些发现推断脓毒症的发病机制可能是由不同的细菌引起的。 宿主对不同病原体的反应。项目3中提出的研究将进一步测试 假设在血管内皮上表达的主要HSPG，即syndecan-1，syndecan-2， 多配体蛋白聚糖-4和磷脂酰肌醇蛋白聚糖-1，与MMP组成功能性联系，赋予不同的结果， 由这些细菌病原体和革兰氏阴性大肠杆菌引起的败血症的凝血病和炎症 大肠杆菌（EC）。该项目还将产生关于HSPG-蛋白复合物的独特知识， 疾病发作和进展。这些研究将集中在小鼠的HSPGs和HS结合蛋白上 和人在由革兰氏阴性和革兰氏阳性病原体引起的脓毒症期间，以及在全身性 炎症反应综合征（SIRS），并可能产生新的潜在的生物标志物和新的方法， 调节脓毒症和SIRS的结果。项目负责人和核心成员的跨学科专业知识 领导者和可用的综合资源将实现对HSPG的机械理解 与调节凝血，凝血病， 炎症以及因涉及不同病原体的感染而导致的SIRS和败血症的结果。

SUMMARY The aims of this project address the central hypothesis of the overall program, that Protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. This research project will investigate the roles of heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs), and matrix metalloproteases (MMPs) in the coagulopathy and inflammation of sepsis. The proposed research engages all of the core facilities of the program and draws on the combined expertise of the Project Leaders and Core Leaders in infection and sepsis, inflammatory biology, coagulation, coagulopathy, proteomics, and glycobiology. From recent literature and preliminary data, HS attached to endothelial HSPGs alters the outcome of sepsis coincident with HSPG shedding from vascular endothelial cells induced by MMPs. Moreover, vascular HS deficiency has opposing effects on the outcomes of sepsis caused by different microbial pathogens including Gram-positive Streptococcus pneumoniae (SPN) and Gram-negative Salmonella enterica Typhimurium (ST). In addition, MMP inhibition affects HSPG shedding and provides a protective role in the pathogenesis of sepsis caused by ST. These findings infer the possibility that the pathogenesis of sepsis may be stratified by different host responses in the context of distinct pathogens. Research proposed in Project 3 will further test the hypothesis that the major HSPGs expressed on the vascular endothelium, namely syndecan-1, syndecan-2, syndecan-4, and glypican-1, compose a functional nexus with MMPs that confer separate outcomes in the coagulopathy and inflammation of sepsis caused by these bacterial pathogens and Gram-negative Escherichia coli (EC). This project will also generate unique knowledge about the repertoire of HSPG-protein complexes in disease onset and progression. The proposed studies will focus on HSPGs and HS-binding proteins in mice and humans during sepsis caused by Gram-negative and Gram-positive pathogens, and in Systemic Inflammatory Response Syndrome (SIRS) and may yield new potential biomarkers and novel approaches to modulating the outcomes of sepsis and SIRS. The interdisciplinary expertise of the Project Leaders and Core Leaders, and the combined resources available, will achieve a mechanistic understanding of HSPG homeostasis and HSPG-protein complex determinants implicated in modulating the coagulation, coagulopathy, inflammation, and outcomes of SIRS and sepsis due to infections involving different pathogens.