Protein Glycosylation in the Coagulopathy and Inflammation of Sepsis

脓毒症凝血障碍和炎症中的蛋白质糖基化

• 批准号: 9916805
• 负责人: JAMEY MARTH
• 金额: $ 254.35万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916805
• 关键词: Acute; Address; Affect; Alkaline Phosphatase; Binding Proteins; Biomedical Research; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Vessels; Blood coagulation; Blood specimen; Cell physiology; Cell surface; Cessation of life; Coagulation Process; Core Facility; Data; Diagnosis; Diagnostic; Disease; Equilibrium; Escherichia coli Infections; Expenditure; Functional disorder; Glycoproteins; Glycoside Hydrolases; Goals; Half-Life; Health Care Costs; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Homeostasis; Human; Immune response; Incidence; Inflammation; Inhibition of Matrix Metalloproteinases Pathway; Investigation; Knowledge; Lead; Lectin Receptors; Life; Link; Matrix Metalloproteinases; Molecular; Mus; N acetylglucosaminidase; Neuraminidase; Outcome; Pathogenesis; Patients; Peptide Hydrolases; Physiological; Plasma; Play; Polysaccharides; Prevalence; Process; Protein Glycosylation; Proteoglycan; Proteomics; Reaction; Research; Research Project Grants; Research Proposals; Role; Salmonella enterica; Salmonella typhimurium; Scientist; Sepsis; Serologic tests; Severities; Structure; Syndrome; Systemic Inflammatory Response Syndrome; Technology; Therapeutic; Tissues; Vascular System; Virulence; aged; beta-Galactosidase; biomedical scientist; comparative; disability; effective therapy; heparin proteoglycan; improved; inflammatory marker; insight; microorganism; mouse model; multidisciplinary; pathogen; pathogenic bacteria; prevent; programs; receptor; receptor function; senescence; septic patients

DESCRIPTION (provided by applicant): The molecular and cellular processes that maintain a physiological balance in blood coagulation and inflammation are acutely altered in sepsis. The resulting coagulopathy and inflammation cause disability and death among a large proportion of sepsis patients throughout the developed and undeveloped world. Millions of patients are diagnosed with sepsis each year, with the associated expenditure of tens of billions of dollars in health care costs. Still, sepsis is increasing in incidence with the prevalence and virulence of infectious pathogens. Lack of sufficient knowledge of the pathophysiology of sepsis including host responses has primarily contributed to the paucity of current treatments. This program project integrates the expertise of multiple biomedical scientists and clinicians whom have recently made potentially transformative and translational discoveries of host responses in sepsis that remodel glycoproteins of the blood and vasculature. This remodeling alters glycan linkages on blood glycoproteins and diminishes heparin sulfate proteoglycan tethering to the vascular wall, resulting in changes to the half-lives, abundance, and functions of blood and vascular glycoproteins with a profound impact on the coagulopathy, inflammation, and lethality of sepsis. Further discoveries that this program project team are poised to make are expected to achieve significant advances in the mechanistic understanding of the life-threatening changes to host blood and vascular systems during sepsis. The program is integrated by a central hypothesis proposing that Protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. The research projects are highly synergistic with interdisciplinary and state of the art technologies that span four core facilities to support three research projects that all address the central hypothesis of the program. The overall objective is to identify and investigate blood and vascular glycoprotein remodeling mechanisms and their multiple effects on coagulopathy, inflammation, and the outcomes of Gram-negative and Gram-positive bacterial sepsis in mice and compared with the underlying Systemic Inflammatory Response Syndrome (SIRS). The program will also incorporate analyses of blood samples from human patients diagnosed with sepsis or SIRS. The research aims encompass investigations of coagulation, tissue coagulopathy, inflammation markers, glycan linkages, serology, pathogen burden, and comparative proteomic analyses of blood samples. Recent findings demonstrate that conserved glycoprotein homeostatic mechanisms differentially modulate the pathogenesis and outcomes of sepsis caused by distinct pathogens, supporting the emerging view that sepsis is not a singular disease process. The specific aims of this program project are further derived from extensive preliminary data that supports the proposed studies. The combined results of this program will generate insights into host responses and mechanisms that modulate the coagulopathy and inflammation of sepsis, and will generate important information needed to develop more effective diagnostic and therapeutic approaches.

描述（由申请人提供）：维持血液凝固和炎症生理平衡的分子和细胞过程在败血症中发生剧烈改变。由此产生的凝血病和炎症导致整个发达和不发达世界的大部分败血症患者的残疾和死亡。每年有数百万患者被诊断患有脓毒症，相关的医疗保健费用支出高达数百亿美元。尽管如此，脓毒症的发病率随着感染性病原体的流行和毒力而增加。缺乏足够的知识，脓毒症的病理生理学，包括主机的反应，主要是导致目前的治疗缺乏。该计划项目整合了多位生物医学科学家和临床医生的专业知识，他们最近对脓毒症中重塑血液和血管系统糖蛋白的宿主反应进行了潜在的变革和转化发现。这种重塑改变了血液糖蛋白上的聚糖键，并减少了硫酸肝素蛋白聚糖与血管壁的束缚，导致血液和血管糖蛋白的半衰期、丰度和功能发生变化，对凝血病、炎症和败血症的致死性产生深远影响。该计划项目团队准备做出的进一步发现有望在脓毒症期间对宿主血液和血管系统的危及生命的变化的机制理解方面取得重大进展。该计划是由一个中心的假设，提出蛋白质糖基化和糖蛋白重塑调节凝血功能障碍和炎症的败血症。这些研究项目与跨学科和最先进的技术高度协同，跨越四个核心设施，支持三个 研究项目，所有解决该计划的中心假设。总体目标是确定和研究血液和血管糖蛋白重塑机制及其对凝血障碍、炎症和革兰氏阴性和革兰氏阳性细菌败血症小鼠结局的多重影响，并与潜在的全身炎症反应综合征（SIRS）进行比较。该计划还将纳入对诊断为败血症或SIRS的人类患者的血液样本的分析。研究目标包括凝血、组织凝血病、炎症标志物、聚糖连接、血清学、病原体负荷和血液样本的比较蛋白质组学分析。最近的研究结果表明，保守的糖蛋白稳态机制差异调节不同病原体引起的脓毒症的发病机制和结果，支持新兴的观点，脓毒症不是一个单一的疾病过程。该计划项目的具体目标进一步来源于支持拟议研究的大量初步数据。该计划的综合结果将产生对调节脓毒症凝血病和炎症的宿主反应和机制的见解，并将产生开发更有效的诊断和治疗方法所需的重要信息。