Endothelial Glycocalyx Degradation during Sepsis in Aging

项目摘要/摘要 脓毒症是人体对感染的破坏性全身反应，全世界有5000多万患者受到影响 每年一次。老年人患脓毒症的风险增加，而且预后更差。 已确诊为脓毒症。虽然许多因素可能导致败血症对老年人的不成比例的影响 患者，最近的研究表明内皮功能障碍对这种差异有重要贡献。 内皮糖萼是一种富含硫酸乙酰肝素(HS)的糖胺多聚糖层，排列在 血管管腔在血管内稳态中起着核心作用。我们的实验室发现， 脓毒症时内皮细胞糖基化降解，导致脓毒症特有的局部血管功能障碍 器官(如肺和肾)损伤。此外，糖萼降解释放生物活性HS 碎裂进入血液循环，对器官功能产生系统性影响。我们之前发现败血症- 释放的、循环中的HS片段选择性地沉积在大脑的记忆中心海马体中。 这些贯穿海马区的HS片段抑制了生长因子脑源性神经营养因子(BDNF) 是学习和记忆的中心，直接导致影响大多数人的持续性认知功能障碍 败血症幸存者。 更好地了解脓毒症内皮细胞糖基化在衰老过程中降解的初步研究 证明循环中的HS水平(一种高度敏感的内皮糖催化降解指标) 在老年患者中最高。一致的是，HS升高在年龄(24个月龄)时更明显 在脓毒症模型中与年轻的(8至12周大)小鼠进行比较。负责这一点的机制 老年患者内皮糖催化降解的严重程度尚不清楚。额外的初步报告 实验表明，这些机制与已知的乙酰肝素酶依赖不同。 年轻患者的内皮糖萼降解。 这项提议将检验以下假设：1)脓毒症内皮细胞的机制 老年患者的糖萼降解与年轻患者不同(即非乙酰肝素酶 依赖)和2)内皮细胞糖基化降解导致局部器官损伤加重。 老年小鼠脓毒症后认知结果较差。关键的是，这项工作将使希本斯蒂尔博士能够扩大 基于他研究危重疾病认知影响的独特专业知识，同时作为他的 在衰老科学领域的新职业。

Project Summary/Abstract Sepsis, the body's injurious systemic response to infection, affects greater than 50 million patients world-wide annually. Older people experience both an increased risk of sepsis onset as well as worse outcomes from established sepsis. While many factors likely contribute to the disproportionate effect of sepsis on older patients, recent studies have suggested important contributions of endothelial dysfunction to this disparity. The endothelial glycocalyx, a heparan sulfate (HS)-rich layer of glycosaminoglycans that lines the vascular lumen, plays a central role in vascular homeostasis. Our laboratory has discovered that the endothelial glycocalyx is degraded during sepsis, leading to local vascular dysfunction characteristic of septic organ (e.g. lung and kidney) injury. Additionally, glycocalyx degradation releases biologically active HS fragments into the circulation, impacting organ function systemically. We have previously found that sepsis- released, circulating HS fragments selectively deposit within the hippocampus, the memory center of the brain. These hippocampal-penetrating HS fragments inhibit brain-derived neurotrophic factor (BDNF), a growth factor central to learning and memory, directly contributing to persistent cognitive dysfunction that affects the majority of sepsis survivors. Preliminary studies to better understand septic endothelial glycocalyx degradation in aging demonstrated that circulating levels of HS (a highly-sensitive measure of endothelial glycocalyx degradation) are highest in older patients. Concordantly, HS elevations were more pronounced in aged (24 month-old) compared to young (8 to 12 week-old) mice in a model of sepsis. The mechanisms responsible for this increased severity of endothelial glycocalyx degradation in older patients is unknown. Additional preliminary experiments suggest they these mechanisms be distinct from the known heparanase-dependence of endothelial glycocalyx degradation in younger patients. This proposal will test the hypotheses that 1) the mechanism responsible for septic endothelial glycocalyx degradation in older patients is distinct from that of younger patients (i.e. non-heparanase dependent) and 2) endothelial glycocalyx degradation is responsible for worsened local organ injury during and poor cognitive outcomes after sepsis in older mice. Critically, this work will allow Dr. Hippensteel to expand upon his unique expertise studying the cognitive effects of critical illness, while serving as a launchpad for his nascent career in the science of aging.