# In vitro modeling of blood brain barrier dysfunction on a chip to elucidate the pathogenesis of cerebral malaria

> **NIH NIH R61** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $827,608

## Abstract

Project Summary
Brain microvascular endothelial cells (BMECs) which line the vascular network of the central nervous system
(CNS) in conjunction with perivascular cells form a specialized barrier termed the blood-brain barrier (BBB) that
regulates the dynamic traffic of select molecules into and out of the CNS. Studies of BBB dysfunction have been
hampered by an inability to perform direct testing in patients and a lack of in vitro models. Analysis of available
putative BMECs from pluripotent stem cell sources reveals that they do not harbor bona fide brain EC molecular
signatures. Using a transcription factor-based reprogramming strategy, we demonstrate that durable and
functional true endothelial cells with BBB traits may be derived. We will use these verified BMECs in the
development of isogenic BBB/on-a-chip devices. Cortical brain organoids derived from patient specific induced
pluripotent cells (IPSC) will be vascularized by matched IPSC derived bona fide BMECs in a microfluidic device.
To explore the potential of this new technology we will investigate the pathobiology of cerebral malaria a severe
disease syndrome that causes neurodisability in 20% of survivors. Red blood cells infected with the Plasmodium
falciparum parasite adhere to the brain microvasculature causing dysfunction. We hypothesize that the parasite
primes the brain endothelial cells for adherence through their “education” by small extracellular vesicles termed
exosomes. This is an established paradigm in cancer biology in which malignant cells educate metastatic
“microniches” to prime for and enhance tumor survival. The exosomes mediate local and systemic intercellular
communication through the horizontal transfer of information in their proteomes. We recently were able to identify
a critical prognosis biomarker for brain metastasis in breast cancer through studies of exosomal cellular uptake
and proteomic analysis. We will analyze the proteomes of exosomes from children with cerebral malaria and
infuse them into our innovative microfluidic-based BBB model. We will monitor in real time how exosomes trigger
BBB dysfunction and subsequently affect IPS-derived brain organoids from patients affected by CM. These
studies will provide new insights into disease pathogenesis and potentially identify new prognosis biomarkers.

## Key facts

- **NIH application ID:** 10488809
- **Project number:** 5R61HL154310-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** LINNIE GOLIGHTLY
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $827,608
- **Award type:** 5
- **Project period:** 2021-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488809

## Citation

> US National Institutes of Health, RePORTER application 10488809, In vitro modeling of blood brain barrier dysfunction on a chip to elucidate the pathogenesis of cerebral malaria (5R61HL154310-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10488809. Licensed CC0.

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