Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis

摘要 这个项目的目标是解决整个计划的中心假设，即蛋白质糖基化和 糖蛋白重塑调节脓毒症的凝血和炎症反应。这项研究项目将 研究硫酸乙酰肝素(HS)、硫酸乙酰肝素蛋白多糖(HSPGs)和基质的作用 金属蛋白酶(MMPs)在脓毒症凝血和炎症中的作用拟议的研究涉及所有 计划的核心设施，并利用项目负责人和核心人员的综合专业知识 在感染和败血症、炎症生物学、凝血、凝血障碍、蛋白质组学和糖生物学方面处于领先地位。 根据最近的文献和初步数据，内皮细胞HSPG上附着的HS改变了脓毒症的结局 与MMPs诱导的血管内皮细胞HSPG脱落相一致。此外，血管HS 缺乏对不同微生物病原体引起的脓毒症的结局有相反的影响，包括 革兰氏阳性肺炎链球菌(SPN)和革兰氏阴性肠炎沙门菌(ST)。 此外，抑制基质金属蛋白酶影响热休克蛋白的脱落，并在脓毒症的发病机制中起到保护作用。 由St.引起。这些发现推测，脓毒症的发病机制可能是由不同的 不同病原体背景下的寄主反应。项目3中提出的研究将进一步测试 假设主要的HSPG表达于血管内皮细胞，即syndecan-1，syndecan-2， Syndecan-4和Glypcan-1与MMP组成了一个功能联系，在 这些细菌和革兰氏阴性杆菌引起的脓毒症的凝血和炎症反应 大肠杆菌(EC)。该项目还将产生关于HSPG-蛋白质复合体的独特知识 疾病的发生和发展。拟议的研究将集中在小鼠的HSPGs和HS结合蛋白上 和人类在脓毒症期间由革兰氏阴性和革兰氏阳性病原体引起的，以及在全身 炎症反应综合征(SIRS)，并可能产生新的潜在生物标志物和新的治疗方法 调节败血症和全身炎症反应综合征的转归。项目负责人和核心人员的跨学科专业知识 领导人和可用的综合资源将实现对HSPG的机械性理解 动态平衡和HSPG-蛋白质复合体决定因素参与调节凝血，凝血障碍， 炎症、全身炎症反应综合征和败血症是由涉及不同病原体的感染引起的。

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.