Protein Glycosylation in the Coagulopathy and Inflammation of Sepsis

总结 脓毒症是一种危及生命的综合征，由血液中有害微生物的存在引起， 组织并导致宿主炎症、凝血病和器官功能障碍。作为死亡的主要原因 在非心脏重症监护室中，败血症的发生率持续增加，但没有新的有效治疗方法 几十年来已经开发了各种疗法。在患者中，死亡率平均为25%，而许多幸存者 经历由血栓形成、灌注不足和高胰岛素血症引起的长期残疾。在全球范围内， 败血症比癌症更普遍，有数百万患者和数十亿美元的医疗保健费用 每年。缺乏脓毒症病理生理学的分子信息主要促成了 缺乏新的和更有效的治疗方法。该计划项目更新提案继续解决这一问题 新方法的问题，以推进脓毒症的知识从描述性的更多的分子 基础该计划保留了科学家和临床医生的专业知识，他们共同努力， 发现病原体和宿主针对的疾病机制和保护策略， 脓毒症的发作和进展。拟议的计划更新利用了以下比较模型： 实验性脓毒症用于发现快速重塑和调节宿主的疾病机制 血液和血管成分。重塑包括糖苷和蛋白水解过程， 对循环和细胞表面的半衰期、定位、丰度和功能的深刻变化 糖蛋白和血小板，与凝血病、炎症和败血症的致死性有关。该计划是 整合的整体假设，蛋白质糖基化和糖蛋白重塑改变 凝血病和败血症炎症。建议的3个项目和4个核心设施将解决这一问题 假设与协同，跨学科，和国家的最先进的方法。项目目标和核心 包括凝血因子，组织血栓形成，炎症， 血清学，以及血液、尿液和组织蛋白质组中的病原体负荷和毒力。迄今为止的调查结果 已经确定了在离散病原体的背景下差异识别和改变脓毒症的机制 包括病原体毒力的变化，支持败血症不是由 单一的疾病机制，并可以分层，以实现诊断和治疗的好处。比较 实验和人类脓毒症的分析将继续进行，因为迄今为止的发现表明， 与病原体分层和患者预后相关的疾病机制标志物。的理由 该方案的目标来自广泛的支持数据和最近的同行评审出版物。 该计划准备做出的其他发现将使机械方面的进一步进展成为可能。 了解脓毒症期间宿主血液和血管系统的危及生命的变化， 开发更有效的诊断和治疗方法所需的重要见解。

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.