Vascular mechanisms of sepsis-induced cognitive dysfunction

脓毒症所致认知功能障碍的血管机制

基本信息

批准号：
10681857
负责人：
Paco S Herson
金额：
$ 72.7万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681857
关键词：
Acceleration Affinity Chromatography Animal Model Animals Binding Proteins Biological Markers Blood Blood - brain barrier anatomy Blood Circulation Blood Vessels Brain Brain Injuries Cause of Death Chronic Circulation Clinical Research Cognitive Collaborations Critical Illness Data Dementia Development Dextrans Electrophysiology (science)Endothelial Cells Endothelium Extravasation Face Functional disorder Glycobiology Glycocalyx Glycosaminoglycans Goals Growth Factor Heparin Heparitin Sulfate Hippocampus Human Impaired cognition Industrialization Infection Interdisciplinary Study International Journals Laboratories Learning Lipopolysaccharides Lung Manuscripts Mediator Memory Memory Loss Methods Modeling Molecular Mus Neurocognitive Outcome Patients Penetration Prions Proteins Proteomics Publishing Role Sepsis Societies Specificity Stream Supportive care Survivors Testing Tissues United States National Academy of Sciences Work blood damage blood-brain barrier permeabilization clinical investigation cohort effective therapy experience experimental study improved injured innovation mortality multidisciplinary neurobehavior novel overexpression patient population prevent prospective response septic septic patients spatial memory sugar therapeutic target tool translational impact uptake

项目摘要

Sepsis, the injurious systemic response to infection, is a major cause of death in both industrialized and developing societies. With advances in supportive care, sepsis mortality has improved, leading to increased recognition of the chronic consequences of this critical illness. Nearly 50% of sepsis survivors experience long- term cognitive impairment, akin to accelerated dementia. Despite the substantial societal burden of septic cognitive impairment, no effective therapies are known to prevent or treat this condition. A multidisciplinary collaboration between the laboratories of Drs. Eric Schmidt (an expert in sepsis and vascular glycobiology) and Paco Herson (an expert in brain injury) recently identified a novel mechanism underlying the development of septic cognitive impairment. As detailed in manuscripts published in 2019 in the Journal of Clinical Investigation and the Proceedings of the National Academy of Sciences, we observed that heparan sulfate (HS) fragments, shed into the circulation during septic degradation of the endothelial glycocalyx, specifically penetrate into only one tissue: the hippocampus, a compartment of the brain responsible for spatial memory formation. Hippocampal-penetrating HS fragments sequester a key growth factor necessary for learning, leading to persistent cognitive impairment in both septic animals and humans. The striking hippocampal specificity of HS extravasation during sepsis prompted our laboratory to pursue additional preliminary experiments using a murine lipopolysaccharide (LPS) model of sepsis. LPS-induced hippocampal blood-brain barrier (BBB) hyperpermeability was specific to HS, as similarly-sized dextrans were unable to penetrate the hippocampus. Heparin affinity chromatography and proteomic analyses identified that LPS selectively induces several HS-binding proteins within the hippocampus, including an endothelial protein previously implicated in paracellular BBB permeability (Prion related protein, Prp). This selective induction of hippocampal HS-binding proteins mirrors the hippocampal specificity of HS extravasation during sepsis. Based upon these preliminary data, we hypothesize that sepsis induces expression of HS-binding proteins (such as Prp) released into the blood stream. These proteins facilitate the selective transport of circulating HS into the hippocampus, leading to cognitive impairment in sepsis survivors. Pursuit of this hypothesis will require mechanistic interrogation of sepsis-induced HS-binding proteins as putative mediators of HS uptake by the hippocampal BBB. To achieve this goal requires a multi-disciplinary team to use cutting-edge molecular tools to assess HS transport in animal models and clinical studies to correlate to the human patient population. We will specifically identify 1) the mechanism of HS accumulation into the hippocampus, 2) the role of circulating prion-related protein in neurocognitive dysfunction following experimental sepsis and 3) correlate circulating HS and Prp with cognitive outcome in human sepsis patients

脓毒症是对感染的伤害性全身反应，是工业化国家和工业化国家死亡的主要原因。发展中社会。随着支持治疗的进步，脓毒症死亡率有所改善，导致脓毒症死亡率增加认识到这种危重疾病的慢性后果。近 50% 的败血症幸存者经历长期术语认知障碍，类似于加速性痴呆。尽管化粪池造成了巨大的社会负担认知障碍，目前尚无有效的疗法可以预防或治疗这种情况。博士实验室之间的多学科合作。埃里克·施密特（Eric Schmidt）（败血症和血管方面的专家）糖生物学）和 Paco Herson（脑损伤专家）最近发现了一种新的机制脓毒症认知障碍的发展。正如 2019 年发表在《Journal of》杂志上的手稿中详细介绍的那样临床研究和美国国家科学院院刊，我们观察到乙酰肝素硫酸盐（HS）碎片，在内皮糖萼的败血性降解过程中流入循环系统，特别地只渗透到一个组织：海马体，大脑的一个部分，负责空间记忆的形成。穿透海马的 HS 片段隔离了生长所需的关键生长因子学习，导致脓毒症动物和人类持续认知障碍。脓毒症期间 HS 外渗的惊人海马特异性促使我们的实验室进行研究使用脓毒症鼠脂多糖（LPS）模型进行额外的初步实验。 LPS诱导的海马血脑屏障 (BBB) 通透性过高是 HS 特有的，因为类似大小的右旋糖酐无法穿透海马体。肝素亲和层析和蛋白质组分析确定 LPS 在海马内选择性诱导多种 HS 结合蛋白，包括内皮蛋白先前涉及细胞旁 BBB 通透性（朊病毒相关蛋白，Prp）。这种选择性诱导海马 HS 结合蛋白反映了脓毒症期间 HS 外渗的海马特异性。基于这些初步数据，我们假设脓毒症诱导 HS 结合蛋白的表达（如 Prp）释放到血流中。这些蛋白质促进选择性转运 HS 循环进入海马体，导致脓毒症幸存者认知障碍。追求这个假设需要对脓毒症诱导的 HS 结合蛋白进行机械询问，将其作为假定的介质海马 BBB 摄取 HS。为了实现这一目标，需要一个多学科团队使用尖端技术用于评估动物模型中 HS 转运的分子工具以及与人类患者相关的临床研究人口。我们将具体确定 1) HS 积累到海马的机制，2) 作用实验性脓毒症后神经认知功能障碍中循环朊病毒相关蛋白的变化和 3) 相关循环 HS 和 Prp 与人类败血症患者的认知结果