# Mechanisms of endothelial dysfunction in cerebral malaria and barrier restorative pathways

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $698,710

## Abstract

Project Abstract
Endothelial activation, dysfunction, and barrier disruption are hallmarks of inflammation-related diseases, such
as malaria, sepsis, and viral hemorrhagic fever. Cerebral malaria is a severe complication of infection with
Plasmodium falciparum malaria parasites. In patients with cerebral malaria, red blood cells infected with
malaria parasites bind within cerebral microvessels leading to microvascular obstruction, thrombosis,
breakdown of the blood-brain barrier (BBB), and severe brain swelling. The molecular mechanisms of how the
complex parasite and host inflammatory stimuli cause breakdown of the blood-brain barrier are only partially
understood, and strategies to restore BBB integrity remain limited. Kinase inhibitors are potential drugs to
stabilize the endothelial barrier following hyperinflammatory damage. This project builds on our recent findings
that specific kinase inhibitors promote endothelial barrier strengthening and protect against thrombin-induced
barrier disruption. In this project, we will investigate the mechanism(s) of action of barrier-protective kinase
inhibitors using in vitro human brain endothelial cell models and study how endothelial cells integrate signals
from host and parasite inflammatory products. Using a new 3D human brain microvessel model, we will also
study how flow disturbances interact with host and parasite stimuli in endothelial activation and barrier
disruption. Finally, we will evaluate the efficacy of barrier-protective kinase inhibitors using a combination of the
in vitro 3D human brain microvessel model and an experimental cerebral malaria (ECM) mouse model. The
proposed studies will study kinase regulation of endothelial barrier integrity and investigate the potential of
kinase inhibitors to stabilize endothelial barrier properties, with the long-term goal of developing new
therapeutic approaches to treat a wide spectrum of clinical disease associated with endothelial dysfunction.

## Key facts

- **NIH application ID:** 10466868
- **Project number:** 5R01AI148802-03
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** JOSEPH DOUGLAS SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $698,710
- **Award type:** 5
- **Project period:** 2020-09-23 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466868

## Citation

> US National Institutes of Health, RePORTER application 10466868, Mechanisms of endothelial dysfunction in cerebral malaria and barrier restorative pathways (5R01AI148802-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10466868. Licensed CC0.

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