Vascular mechanisms of sepsis-induced cognitive dysfunction

脓毒症所致认知功能障碍的血管机制

• 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
• 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

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，一种对感染的破坏性全身反应，是工业化和工业化国家死亡的主要原因 发展中社会。随着支持性护理的进步，脓毒症的死亡率有所改善，导致 认识到这一危重疾病的慢性后果。近50%的脓毒症幸存者经历了长期- 术语认知障碍，类似于加速痴呆症。尽管败血症带来了巨大的社会负担 认知障碍，目前还没有有效的治疗方法来预防或治疗这种疾病。 埃里克·施密特博士(败血症和血管方面的专家)的实验室之间的多学科合作 糖生物学)和帕科·赫森(脑损伤专家)最近发现了一种新的机制， 败血症认知功能障碍的发展。如2019年发表在《华尔街日报》上的手稿所述 临床研究和美国国家科学院院刊，我们观察到肝素 硫酸盐(HS)片段，在内皮糖催化剂败血症降解过程中进入循环， 特定地只穿透到一种组织：海马体，这是大脑中负责空间分布的一个隔间 记忆的形成。贯穿海马区的HS片段隔离了一个关键的生长因子 学习，导致败血症动物和人类的持续性认知障碍。 脓毒症时HS渗出的显著海马区特异性促使我们实验室研究 使用小鼠脂多糖(LPS)脓毒症模型进行的其他初步实验。内毒素诱导 海马血脑屏障(BBB)的高通透性是HS所特有的，与类似大小的右旋糖苷一样 无法穿透海马体。肝素亲和层析和蛋白质组学分析证实 内毒素选择性地诱导海马区内的几种HS结合蛋白，包括一种内皮蛋白 先前与细胞旁血脑屏障通透性有关(Prion相关蛋白，PRP)。这种选择性的诱导 海马区HS结合蛋白反映了败血症时HS渗出的海马区特异性。 根据这些初步数据，我们假设败血症诱导HS结合蛋白的表达 (如PRP)释放到血液中。这些蛋白质有助于选择性地转运 将HS循环到海马体，导致败血症幸存者的认知障碍。追求这一点 假说将需要对脓毒症诱导的HS结合蛋白作为假定的介体进行机械性询问 海马区BBB对HS的摄取。要实现这一目标，需要一支多学科的团队来使用尖端技术 评估HS在动物模型和临床研究中转运的分子工具与人类患者的相关性 人口。我们将具体确定1)HS在海马区蓄积的机制，2)作用 实验性脓毒症后神经认知功能障碍患者循环蛋白的变化及其相关性 人类脓毒症患者循环HS和PRP与认知结局的关系