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

基本信息

批准号：
10475586
负责人：
JAMEY MARTH
金额：
$ 267.7万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10475586
关键词：
Address Age Alkaline Phosphatase Biological Markers Blood Blood Coagulation Disorders Blood Coagulation Factor Blood Platelets Blood Vessels Cause of Death Cell surface Cessation of life Clinical Core Facility Data Data Analyses Development Diagnosis Diagnostic Disease Disease Marker Disease stratification Endothelium Experimental Models Factor XI Frequencies Functional disorder Galactose Genetic Glycocalyx Glycoproteins Glycoside Hydrolases Glycosides Goals Half-Life Health Health Care Costs Hemostatic function Heparitin Sulfate Hepatocyte Human Hyaluronan Hyaluronic Acid Immune response Incidence Infection Inflammation Innate Immune Response Interleukin-10 Investigation Knowledge Kupffer Cells Lectin Lectin Receptors Life Link Malignant Neoplasms Membrane Glycoproteins Molecular Neuraminidase Organ Outcome Pathogenesis Patients Peer Review Plasma Polysaccharides Process Prognosis Protein Glycosylation Proteins Proteome Proteomics Protocols documentation Publications Regulation Research Role Salmonella Sampling Scientist Sepsis Serology Serum Severity of illness Stratification Survivors Syndrome Therapeutic Thrombosis Tissues Urine Vascular System Vascular remodeling Virulence biomedical scientist comparative data acquisition disability disease prognosis effective therapy experience experimental analysis human disease hypoperfusion insight macrophage microorganism mortality novel novel marker novel strategies pathogen pathogenic bacteria patient prognosis prognostic programs receptor senescence septic patients vascular factor

Address Age Alkaline Phosphatase Biological Markers Blood Blood Coagulation Disorders Blood Coagulation Factor Blood Platelets Blood Vessels Cause of Death Cell surface Cessation of life Clinical Core Facility Data Data Analyses Development Diagnosis Diagnostic Disease Disease Marker Disease stratification Endothelium Experimental Models Factor XI Frequencies Functional disorder Galactose Genetic Glycocalyx Glycoproteins Glycoside Hydrolases Glycosides Goals Half-Life Health Health Care Costs Hemostatic function Heparitin Sulfate Hepatocyte Human Hyaluronan Hyaluronic Acid Immune response Incidence Infection Inflammation Innate Immune Response Interleukin-10 Investigation Knowledge Kupffer Cells Lectin Lectin Receptors Life Link Malignant Neoplasms Membrane Glycoproteins Molecular Neuraminidase Organ Outcome Pathogenesis Patients Peer Review Plasma Polysaccharides Process Prognosis Protein Glycosylation Proteins Proteome Proteomics Protocols documentation Publications Regulation Research Role Salmonella Sampling Scientist Sepsis Serology Serum Severity of illness Stratification Survivors Syndrome Therapeutic Thrombosis Tissues Urine Vascular System Vascular remodeling Virulence biomedical scientist comparative data acquisition disability disease prognosis effective therapy experience experimental analysis human disease hypoperfusion insight macrophage microorganism mortality novel novel marker novel strategies pathogen pathogenic bacteria patient prognosis prognostic programs receptor senescence septic patients vascular factor

展开

项目摘要

SUMMARY Sepsis is life-threatening syndrome caused by the presence of harmful microorganisms in the blood and tissues and resulting in host inflammation, coagulopathy and organ dysfunction. As the leading cause of death in non-cardiac intensive care units, the incidence of sepsis continues to increase while no new effective therapies have been developed in decades. Among patients, mortality averages 25%, while many survivors experience long-term disabilities caused by thrombosis, hypoperfusion, and hyperinﬂammation. Globally, sepsis is more prevalent than cancer with millions of patients and billions of dollars of health care costs annually. Lack of molecular information of the pathophysiology of sepsis has primarily contributed to the paucity of new and more effective treatments. This program project renewal proposal continues to address this problem with novel approaches to advance the knowledge of sepsis from a descriptive to a more molecular basis. The program retains the expertise of scientists and clinicians whom together are making transformative discoveries of disease mechanisms and protective strategies targeted by the pathogen and the host in the onset and progression of sepsis. The proposed program renewal leverages comparative models of experimental sepsis applied to the discovery of disease mechanisms that rapidly remodel and regulate host blood and vascular components. Remodeling includes glycosidic and proteolytic processes that cause profound changes to the half-lives, localization, abundance, and functions of circulating and cell surface glycoproteins and platelets, linked to the coagulopathy, inflammation, and lethality of sepsis. The program is integrated by the overall hypothesis that Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. The three projects and four core facilities proposed will address this hypothesis with synergistic, interdisciplinary, and state-of-the-art approaches. Aims of the projects and cores encompass comparative molecular investigations of coagulation factors, tissue thrombosis, inflammation, serology, and pathogen burden and virulence among blood, urine, and tissue proteomes. Findings thus far have identified mechanisms that differentially identify and alter sepsis in the context of discrete pathogens including changes in pathogen virulence, supporting the emerging view that sepsis does not arise from a singular disease mechanism and may be stratified to achieve diagnostic and therapeutic benefits. Comparative analyses of experimental and human sepsis will continue as findings thus far have indicated conserved markers of disease mechanisms linked to stratification by pathogen and patient prognosis. The rationale for the aims of this program are derived from extensive supporting data and recent peer-reviewed publications. Additional discoveries that this program is poised to make will enable further advances in the mechanistic understanding of the life-threatening changes to host blood and vascular systems during sepsis and generate significant insights needed to develop more effective diagnostics and therapeutics.

概括败血症是由于血液中存在有害微生物而引起的威胁生命的综合征组织和导致宿主注射，凝血病和器官功能障碍。作为死亡的主要原因在非心脏重症监护病房中，败血症的事件继续增加，而没有新的有效性几十年来已经开发出疗法。在患者中，死亡率平均为25％，而许多人浮出水面由于血栓形成，灌注不良和超蛋白流量引起的长期疾病。在全球败血症比癌症更为普遍，有数百万患者和数十亿美元的医疗保健费用单程。缺乏败血症病理生理学的分子信息主要有助于缺乏新的，更有效的治疗方法。该计划项目更新提案继续解决此问题新型方法的问题将败血症的知识从描述性提高到更分子基础。该计划保留了科学家和临床医生的专家病原体和宿主针对的疾病机制和受保护策略的发现败血症的发作和进展。提议的计划更新利用了比较模型实验性败血症应用于迅速重塑和调节宿主的疾病机制的发现血液和血管成分。重塑包括引起的糖苷和蛋白水解过程半衰期的深刻变化，循环和细胞表面的局部化，抽象和功能糖蛋白和血小板与败血症的凝血病，感染和致死性有关。该程序是通过总体假设的整体假设，即蛋白质糖基化和糖蛋白重塑改变了脓毒症的凝血病和炎症。提出的三个项目和四个核心设施将解决此问题具有协同，跨学科和最先进的方法的假设。项目和核心的目的包括对凝血因子，组织血栓形成，炎症的比较分子研究血清学和病原体伯嫩和病毒中的血液，尿液和组织蛋白质组织中的病毒。迄今为止的发现已经确定了在离散病原体的背景下对不同识别和改变败血症的机制包括病原体病毒的变化，支持败血症的新兴观点不是由奇异的疾病机制，可以分层以实现诊断和治疗益处。比较迄今为止的发现将继续进行实验和人类败血症的分析与病原体和患者预后相关的疾病机制标记。理由该计划的目的来自广泛的支持数据和最近经过同行评审的出版物。该程序中毒以实现的其他发现将使机理进一步发展了解败血症期间宿主和血管系统的威胁生命的变化并产生开发更有效的诊断和治疗所需的重要见解。