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

> **NIH NIH K08** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $182,296

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10485286
- **Project number:** 5K08GM144788-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Robert P Richter
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $182,296
- **Award type:** 5
- **Project period:** 2021-09-10 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485286

## Citation

> US National Institutes of Health, RePORTER application 10485286, Mechanisms driving endothelial angiopoietin-2 expression and vascular dysfunction during pediatric sepsis (5K08GM144788-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10485286. Licensed CC0.

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