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Targeting circulating endothelial glycocalyx fragments to reduce septic encephalopathy

靶向循环内皮糖萼片段以减少脓毒性脑病

基本信息

批准号：
9922971
负责人：
Paco S Herson
金额：
$ 43.9万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922971
关键词：
Acute Behavioral Beta-glucuronidase Binding Biological Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain-Derived Neurotrophic Factor Cause of Death Characteristics Charge Chronic Cognition Collaborations Critical Care Dementia Development Diagnostic Distant Electrophysiology (science)Encephalopathies Endothelium Endotoxemia Exhibits Face Functional disorder Glycobiology Glycocalyx Glycosaminoglycans Growth Factor Heparitin Sulfate Hippocampus (Brain)Human Industrialization Infection Injury Injury to Kidney International Interruption Investigation Laboratories Learning Lipopolysaccharides Long-Term Potentiation Mass Spectrum Analysis Measures Mediating Mediator of activation protein Memory Modeling Modernization Morbidity - disease rate Mus Neurocognitive Neurocognitive Deficit Neuronal Injury Oligosaccharides Organ Outcome Pathway interactions Patients Penetration Pharmacology Phenotype Plasma Process Productivity Research Personnel Residual state Resolution Sampling Sepsis Signal Pathway Signal Transduction Slice Societies Structure Surface Plasmon Resonance Survivors Synaptic plasticity Testing Therapeutic Therapeutic Intervention Time Transgenic Organisms base cecal ligation puncture clinically relevant cohort conditioned fear experience experimental study extracellular heparanase human mortality improved in vivo intraperitoneal lung injury mouse model neurocognitive test novel organ injury polymicrobial sepsis prevent response septic septic patients sugar therapeutic target vascular bed

项目摘要

PROJECT SUMMARY/ABSTRACT Sepsis is a major cause of death and morbidity in both developing and industrialized societies. While great effort has been dedicated to the study of acute organ injury during sepsis, little is known about the mechanisms underlying the chronic morbidities faced by sepsis survivors. One such morbidity is septic neurocognitive dysfunction (also known as chronic septic encephalopathy), a common, severe illness characterized by the accelerated onset of dementia. Recently, the laboratories of Dr. Eric Schmidt (with extensive expertise in the study of sepsis and glycobiology) and Dr. Paco Herson (with extensive expertise in the study of brain injury) have partnered to establish a mouse model of septic neurocognitive dysfunction. This model has allowed the Schmidt and Herson laboratories to explore a novel hypothesis: that septic degradation of the systemic endothelial glycocalyx (a heparan sulfate (HS)-rich layer lining the vascular lumen) releases biologically-active, circulating HS fragments capable of penetrating the hippocampus and disrupting growth factor signaling pathways implicated in cognition. This newly-created collaboration will explore this hypothesis by performing ex vivo electrophysiological studies of living mouse hippocampi, in vivo mechanistic investigations of neurocognitive dysfunction in mouse survivors of endotoxemia or polymicrobial sepsis, and mass spectrometry studies of human plasma samples collected from a cohort of septic patients who underwent rigorous testing of neurocognitive function after sepsis resolution. This novel proposal, which departs from the “hyperinflammatory” dogma of septic organ injury, promises to identify a mechanistic pathway that is not only responsible for the development of septic neurocognitive dysfunction, but is amenable to therapeutic targeting even in established sepsis.

项目总结/摘要脓毒症是发展中国家和工业化国家死亡和发病的主要原因。而大脓毒症引起的急性器官损伤一直是国内外研究的热点，但其机制尚不清楚脓毒症幸存者面临的慢性发病率的基础。脓毒性神经认知障碍就是其中之一功能障碍（也称为慢性脓毒性脑病），一种常见的严重疾病，其特征是加速痴呆症的发作最近，Eric施密特博士（在生物医学领域拥有丰富的专业知识）的实验室脓毒症和糖生物学研究）和Paco Herson博士（在脑损伤研究方面具有广泛的专业知识）已经合作建立了脓毒性神经认知功能障碍的小鼠模型。这种模式允许施密特和赫森实验室探索一个新的假设：内皮糖萼（衬于血管腔的富含硫酸乙酰肝素（HS）的层）释放生物活性，能够穿透海马并破坏生长因子信号传导的循环HS片段与认知有关的通路这个新创建的合作将通过执行来探索这一假设。活小鼠海马的离体电生理学研究，内毒素血症或多微生物败血症小鼠存活者的神经认知功能障碍和质谱对从一组脓毒症患者中采集的人血浆样本进行了研究，这些患者接受了严格的脓毒症消退后的神经认知功能。这一新颖的提议， “高度炎症”的教条，脓毒性器官损伤，承诺确定一个机制途径，不仅是负责脓毒性神经认知功能障碍的发展，但适合治疗靶向即使是已经确诊的败血症