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Endothelial Glycocalyx Degradation during Sepsis in Aging

Award Number: R03AG074056
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Endothelial Glycocalyx Degradation during Sepsis in Aging - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	2	8/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $155,500 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	2	4/4/2022	NON-COMPETING CONTINUATION	$155,500
														Subtotal = $155,500

Issue Date FY: 2021 ( Subtotal = $155,500 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	1	7/14/2021	NEW	$155,500
														Subtotal = $155,500

Grand Total All Awards = $311,000

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Endothelial Glycocalyx Degradation during Sepsis in Aging

Award Number: R03AG074056

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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