Endothelial Glycocalyx Degradation during Sepsis in Aging
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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.
