Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis

项目3：硫酸乙酰肝素蛋白多糖在脓毒症发病机制中的作用

• 批准号: 9072755
• 负责人: Jeffrey D Esko
• 金额: $ 54.16万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072755
• 关键词: Address; Affect; Animals; Binding; Binding Proteins; Biological; Biology; Biomedical Research; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Vessels; Blood coagulation; Bone Marrow Transplantation; Cessation of life; Coagulation Process; Core Facility; Data; Disease Progression; Dropout; Endothelial Cells; Escherichia coli; Escherichia coli Infections; Extravasation; Gap Junctions; Glycobiology; Glycoproteins; Glypican; Hematology; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Homeostasis; Human; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Knowledge; Lethal Dose 50; Leukocytes; Literature; Matrix Metalloproteinase Inhibitor; Measures; Medical; Metalloproteases; Morbidity - disease rate; Mus; Mutation; N-acetylglucosamine deacetylase; Onset of illness; Organ; Outcome; Pathogenesis; Pathology; Patients; Plasma; Plasma Proteins; Play; Predisposition; Protein Glycosylation; Proteins; Proteomics; Research; Research Project Grants; Research Proposals; Resources; Role; Salmonella enterica; Sepsis; Sepsis Syndrome; Severities; Source; Streptococcus pneumoniae; Structure; Syndrome; System; Testing; Tissues; Vascular Endothelial Cell; Vascular Endothelium; Wild Type Mouse; disability; fibroglycan; inflammatory marker; inhibitor/antagonist; microbial; migration; mortality; mouse model; mutant; novel strategies; pathogen; potential biomarker; prevent; programs; protein complex; proteoglycan core protein; research study; sulfotransferase; syndecan; syndecan-4

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.

概括 该项目的目的涉及整个程序的核心假设，该蛋白质糖基化和 糖蛋白重塑调节败血症的凝血病和炎症。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（HSPGS）和基质的作用 脓毒症的凝血病和炎症中的金属蛋白酶（MMP）。拟议的研究参与了所有 该计划的核心设施，并借鉴了项目领导者和核心的综合专业知识 感染和败血症，炎症生物学，凝结，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中，内皮HSPG附加的HS改变了败血症的结果 与MMP诱导的血管内皮细胞中的HSPG脱落的同时发生。此外，血管HS 缺乏症对不同的微生物病原体引起的败血症的结局产生了相反的影响 革兰氏阳性肺炎链球菌（SPN）和革兰氏阴性沙门氏菌Typhimurium（ST）。 另外，MMP抑制会影响HSPG脱落，并在败血症的发病机理中发挥保护作用 由st。这些发现推断了败血症的发病机理可以通过不同的 宿主反应在不同的病原体的背景下。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， Syndecan-4和Glypican-1与MMP建立功能性联系 由这些细菌病原体和革兰氏阴性大肠造成的败血症的凝血病和炎症 大肠杆菌（EC）。该项目还将在HSPG蛋白复合物中产生独特的知识 疾病发作和进展。拟议的研究将重点放在小鼠中的HSPG和HS结合蛋白上 在由革兰氏阴性和革兰氏阳性病原体引起的败血症期间的人类和人类 炎症反应综合征（SIRS），可能会产生新的潜在生物标志物和新颖的方法 调节败血症和先生的结果。项目负责人和核心的跨学科专业知识 领导者以及可用的合并资源将对HSPG实现机械理解 稳态和HSPG蛋白质复合物决定因素，与调节凝结的凝结蛋白病有关， 由于感染涉及不同病原体的感染引起的炎症以及SIRS和败血症的结局。