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Mechanisms driving endothelial angiopoietin-2 expression and vascular dysfunction during pediatric sepsis

Award Number: K08GM144788
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/10/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Mechanisms driving endothelial angiopoietin-2 expression and vascular dysfunction during pediatric sepsis - This K08 proposal describes a 5-year research training program that will prepare the candidate for a career as an independent, NIH-funded translational scientist focused on mechanisms driving sepsis-mediated vascular disease. The scientific premise for the aims is that vascular endothelial dysfunction is a key driver of organ injury in pediatric sepsis. Morbidity and mortality remain unacceptably high in pediatric sepsis despite advances in modern medicine, principally due to knowledge gaps in the mechanisms driving vascular disease during sepsis. Endothelial cell-derived angiopoietin-2 (Ang-2) has emerged as a critical promoter of vascular injury and organ impairment in sepsis through its antagonism of the endothelial Tie2 receptor. Plasma Ang-2 levels are significantly elevated in children with sepsis and are associated with measures of organ injury and outcomes. Preliminary data suggest that heparan sulfate cleavage from the surface glycocalyx of flow conditioned primary human lung microvascular endothelial cells promotes Ang-2 expression, implicating a novel paradigm by which Ang-2 is upregulated in sepsis. Preliminary data and prior work also suggest that inactivation of liver kinase B1 (LKB1) and downstream adenosine-monophosphate-activated protein kinase (AMPK) may be integral in this process. Further, the candidate discovered that Ang-2 is bound to the surface of exosomes isolated from plasma of septic children, suggesting that exosomal Ang-2 may significantly contribute to vascular disease and organ injury during sepsis. Together, these data support the novel mechanistic hypothesis that enzymatic heparan sulfate erosion from the endothelial glycocalyx during pediatric sepsis upregulates expression of Ang-2 that, when bound to exosomes, has potent vascular destabilizing effects. To test this hypothesis, in vitro, ex vivo, and clinical studies will be performed in the following two aims. Aim 1: Test the hypothesis that glycocalyx heparan sulfate erosion increases Ang-2 expression from flow conditioned human lung microvascular endothelial cells via attenuated LKB1 activity and downstream AMPK pathway signaling. Aim 2: Test the hypothesis that exosomal Ang-2 (a) is biomarker for organ injury and clinical outcomes in pediatric sepsis and (b) promotes endothelial permeability via Tie2 receptor antagonism. Harnessing the combined expertise of the candidate’s mentoring team and utilizing the wealth of resources available at the candidate’s institution, the candidate will train in advanced translational science techniques germane to the completion of these aims, including microvascular flow modeling, nanoparticle tracking analysis and characterization with flow cytometry, and electric cell-substrate impedance sensing. The proposed research program has defined benchmarks that will facilitate the candidate’s career advancement and will culminate in the submission of an R01 to continue uncovering the mechanisms driving vascular disease in pediatric sepsis that will foster the discovery of novel therapeutics.


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: 2025 ( Subtotal = $188,676 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	5	8/25/2025	NON-COMPETING CONTINUATION	$188,676
														Subtotal = $188,676

Issue Date FY: 2024 ( Subtotal = $188,676 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	4	8/28/2024	NON-COMPETING CONTINUATION	$188,676
														Subtotal = $188,676

Issue Date FY: 2023 ( Subtotal = $182,296 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	3	8/18/2023	NON-COMPETING CONTINUATION	$182,296
														Subtotal = $182,296

Issue Date FY: 2022 ( Subtotal = $182,296 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	2	8/15/2022	NON-COMPETING CONTINUATION	$182,296
														Subtotal = $182,296

Issue Date FY: 2021 ( Subtotal = $188,236 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	1	9/8/2021	NEW	$188,236
														Subtotal = $188,236

Grand Total All Awards = $930,180

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Mechanisms driving endothelial angiopoietin-2 expression and vascular dysfunction during pediatric sepsis

Award Number: K08GM144788

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/10/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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