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.

项目摘要/摘要败血症是发展中国家和工业化社会的死亡和发病率的主要原因。虽然很棒努力一直致力于研究败血症期间急性器官损伤的研究，对这些机制知之甚少败血症存活所面临的慢性病的基础。一种这样的发病率是化脓性神经认知功能障碍（也称为慢性败血性脑病），一种常见的严重疾病，其为特征加速痴呆发作。最近，埃里克·施密特（Eric Schmidt）博士的实验室（拥有广泛的专业知识败血症和糖生物学的研究）和Paco Herson博士（在脑损伤研究方面具有广泛的专业知识）已经建立了败血性神经认知功能障碍的小鼠模型。该模型允许 Schmidt和Herson实验室探索一个新的假设：系统性的化粪池降解内皮糖脂（硫酸乙酰肝素（HS） - 富含血管腔的富含层）释放生物活性，循环的HS片段能够穿透海马并破坏生长因子信号传导认知实施的途径。这种新创建的合作将通过执行该假设来探讨这一假设活体小鼠海马的体内电生理研究，体内机械研究内毒性血症或多数症败血症和质谱法的小鼠存活中的神经认知功能障碍从一群接受严格测试的化粪池患者中收集的人血浆样品的研究败血症后神经认知功能。这个小说的提议，偏离了化粪池损伤的“高炎”教条，有望确定不仅是的机械途径负责败血性神经认知功能障碍的发展，但可以接受治疗靶向即使在已建立的败血症中。