Protein Glycosylation in the Coagulopathy and Inflammation of Sepsis

描述（由申请人提供）：维持凝血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。由此产生的凝血功能障碍和炎症在发达国家和不发达国家的大部分败血症患者中导致残疾和死亡。每年有数百万患者被诊断为败血症，相关的医疗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的增加而增加。缺乏足够的败血症病理生理学知识，包括宿主反应，是目前治疗方法缺乏的主要原因。该项目整合了多位生物医学科学家和临床医生的专业知识，他们最近在败血症中重塑血液和脉管系统糖蛋白的宿主反应方面取得了潜在的变革和转化发现。这种重塑改变了糖蛋白上的聚糖键，减少了硫酸肝素蛋白聚糖粘附在血管壁上，导致血液和血管糖蛋白的半衰期、丰度和功能的改变，对凝血功能、炎症和败血症的致死率有深远的影响。该项目团队准备进行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。该计划整合了一个中心假设，提出蛋白质糖基化和糖蛋白重塑调节凝血病和败血症的炎症。这些研究项目是高度协同的跨学科和最先进的技术，跨越四个核心设施来支持三个

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.