# Molecular mechanism mediating apicobasal brain endothelial cells polarity in cerebral cavernous malformation type 3-lesion

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $419,549

## Abstract

Brain vascular malformations and blood-brain barrier defects represent important
substrates for developing stroke, epilepsy and other neurological diseases. The most
common type of brain malformation closely associated with stroke are the cerebral
cavernous malformations (CCMs), which affect approximately 0.5% of the population.
Recognized as inherited and sporadic, CCMs are characterized as a single or multi-cluster
of enlarged capillary-like channels with a single layer of endothelium and without
intervening brain parenchyma. There are specific alterations in the brain endothelial
barrier components that ultimately lead to vascular hyperpermeability, extravasation of red
cells and a neuroinflammatory response. Although significant progress has been made in
defining the genetic mutations involved in the inherited CCM3 form, the intra- and
intercellular pathogenic mechanisms responsible for vascular injury are still largely
unknown. One robust change in brain endothelial cell phenotype is a defect in cell polarity
that affects the cell response to environmental stimuli and may progress the vascular
injury. The proposed study is designed to elucidate critical molecular events involved in
regulation of apicobasal polarity in CCM3 conditions. It will highlight the link between
CCM3 and the cell polarity complex Par3/Par6/aPKC, identified by our screening analysis
to be highly impacted by loss of CCM3 function in brain endothelial cells. Specifically, it
will evaluate structural and functional alterations in the apicobasal polarity of brain
endothelial cells in conditions of modified expression of CCM3 and CCM3 lesions.
Collectively, these studies will provide information related to potential causes of leakiness
and hemorrhage in CCM3 lesions, offer the new insights into the maintenance of brain
endothelial barrier that is relevant also to multiple disease states and will, hopefully,
elucidate novel therapeutic strategies to restore vascular permeability.

## Key facts

- **NIH application ID:** 10526456
- **Project number:** 1R21NS126895-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $419,549
- **Award type:** 1
- **Project period:** 2022-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526456

## Citation

> US National Institutes of Health, RePORTER application 10526456, Molecular mechanism mediating apicobasal brain endothelial cells polarity in cerebral cavernous malformation type 3-lesion (1R21NS126895-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10526456. Licensed CC0.

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