Endothelial Glycocalyx Degradation during Sepsis in Aging

项目概要/摘要 脓毒症是机体对感染的损伤性全身反应，在全世界影响着超过5000万患者 每年。老年人经历脓毒症发作的风险增加以及更糟糕的结果， 确诊败血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， 对于患者，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，一种富含硫酸乙酰肝素（HS）的糖胺聚糖层，排列在内皮细胞的周围。 血管腔，在血管稳态中起着核心作用。我们的实验室发现， 内皮糖萼在脓毒症期间降解，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 碎片进入循环系统影响器官功能我们以前发现败血症- 释放的、循环的HS片段选择性地存款在海马体（大脑的记忆中心）内。 这些穿透海马的HS片段抑制脑源性神经营养因子（BDNF），一种生长因子 中枢学习和记忆，直接导致持续的认知功能障碍，影响大多数 脓毒症幸存者 更好地了解衰老过程中脓毒性内皮糖萼降解的初步研究 证明循环中HS水平（内皮糖萼降解的高度敏感指标） 在老年患者中最高。一致地，HS升高在老年（24月龄）中更明显。 与脓毒症模型中的年轻（8至12周龄）小鼠相比。对此负责的机制 老年患者内皮糖萼降解的严重程度增加尚不清楚。补充初步 实验表明，这些机制不同于已知的乙酰肝素酶依赖性， 年轻患者的内皮糖萼降解。 该提案将测试以下假设：1）脓毒症内皮细胞的机制 老年患者的糖萼降解不同于年轻患者（即非乙酰肝素酶 依赖性）和2）内皮糖萼降解是导致局部器官损伤恶化的原因 老年小鼠脓毒症后认知功能低下。重要的是，这项工作将使希彭斯蒂尔博士 在他独特的专业知识研究的认知影响的重大疾病，而作为一个发射台，他的 在衰老科学方面的新生事业

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.