# Investigating the molecular determinants of cerebral cavernous malformations downstream of MEKK3-KLF2/4 signaling

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $10,765

## Abstract

Project Summary:
Cerebral cavernous malformations (CCMs) are thin-walled, dilated vascular abnormalities that occur
predominantly in the CNS and are a major cause of hemorrhagic strokes and seizures. Presently, there are no
medical therapies for this progressive disease other than invasive neurosurgery. CCMs are caused by genetic
mutations that result in the loss of a heterotrimeric adaptor complex required to negatively regulate MEKK3
signaling and the expression of the KLF2 and KLF4 transcription factors in brain endothelial cells. Recently, we
have identified endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical upstream stimulators
of MEKK3 signaling. However, the downstream effectors of this pathway relevant to disease pathogenesis
have yet to be identified. In the neonatal mouse model of CCM disease, we have observed increased
transcription of ADAMTS metalloproteases and ADAMTS-mediated processing of the ECM proteoglycan,
versican, as early events in CCM development. This proposal will test the hypothesis that MEKK3-KLF2/4
signaling regulates the matrix environment, mediating versican processing by ADAMTS proteases, to promote
CCM formation. Through the use of in vivo genetic mouse models and in vitro model systems, we will
investigate the role of ADAMTS proteases (Aim 1) and their substrate, versican (Aim 2), as candidate
downstream targets of this causal MEKK3 pathway. These studies are expected to yield new insights into the
molecular molecules required to drive lesion genesis and findings may be used to direct the development of
mechanism-based therapeutics for CCM disease.

## Key facts

- **NIH application ID:** 10062836
- **Project number:** 5F31NS115256-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Courtney Hong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $10,765
- **Award type:** 5
- **Project period:** 2019-12-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062836

## Citation

> US National Institutes of Health, RePORTER application 10062836, Investigating the molecular determinants of cerebral cavernous malformations downstream of MEKK3-KLF2/4 signaling (5F31NS115256-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10062836. Licensed CC0.

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