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

败血症是对感染的有害系统性反应，是工业化和发展中的社会。随着支持护理的进步，败血症的死亡率有所提高，导致增加认识到这种重症疾病的慢性后果。将近50％的败血症幸存者经历了悠久的经历术语认知障碍，类似于加速痴呆。尽管化粪池的社会负担很大认知障碍，尚无有效的疗法可以预防或治疗这种情况。 DRS实验室之间的多学科合作。埃里克·施密特（Eric Schmidt）（败血症和血管专家糖生物学）和Paco Herson（脑损伤专家）最近确定了一种新的机制化粪池认知障碍的发展。如2019年在《杂志》上发表的手稿中所详述临床调查和国家科学院的会议录，我们观察到乙par虫硫酸盐（HS）片段，在内皮糖脂的化粪池降解期间脱落到循环中，特别渗透到一个组织中：海马，一个负责空间的大脑的隔室内存形成。海马 - 渗透HS片段隔离了所需的关键生长因子学习，导致化脓性动物和人类的持续认知障碍。败血症期间HS溢出的惊人海马特异性促使我们的实验室追求使用败血症的鼠脂多糖（LPS）模型的其他初步实验。 LPS引起的海马血脑屏障（BBB）超透明度特定于HS，因为类似大小的右旋无法穿透海马。肝素亲和力色谱和蛋白质组学分析确定 LPS选择性诱导海马内的几种HS结合蛋白，包括内皮蛋白先前与细胞细胞BBB渗透性有关（Prion与PRP）。这种选择性诱导海马HS结合蛋白反映了败血症期间HS渗出的海马特异性。基于这些初步数据，我们假设败血症诱导HS结合蛋白的表达（例如PRP）释放到血液中。这些蛋白质有助于选择性运输将HS循环到海马，导致败血症幸存者的认知障碍。追求这个假设将需要对败血症诱导的HS结合蛋白作为推定的介体的机械审问海马BBB的HS吸收。为了实现这一目标，需要一个多学科的团队使用尖端评估动物模型和临床研究中HS转运的分子工具与人类患者相关人口。我们将特别识别1）HS积累到海马的机制，2）实验性败血症后神经认知功能障碍中循环prion相关的蛋白质和3）相关在人类败血症患者中循环HS和PRP具有认知结果