# Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

> **NIH NIH P01** · DUKE UNIVERSITY · 2020 · $1,353,471

## Abstract

Signaling Aberrations and Cerebral Cavernous Malformations Pathogenesis. In the first cycle of this program project our collaborative group has made significant discoveries concerning CCM pathogenesis. In this renewal we will follow up these discoveries towards a scientifically based therapy. Recent data from multiple laboratories in our program converge on a model in which somatically mutated, CCM-deficient endothelial cells poison the peri-lesional environment to recruit non-deficient cells into the growing lesion. We will investigate the molecular and cellular basis for this non-cell autonomous pathological mechanism, including single-cell genomic and transcriptomic analyses in mouse and human lesions and mechanistic studies in mouse models. We have also discovered that endothelial cells within murine and human CCMs express markedly increased levels of thrombomodulin and endothelial protein C receptor which leads to activation of endogenous anti-coagulant protein C. This discovery provides a new target for lesional hemorrhage, the most clinically significant phenotype associated with CCM. Importantly, to enable these and other studies we have generated new, more robust CCM mouse models that exhibit both rapid lesion growth and lesional hemorrhage. We have also identified an unexpected and novel signaling aberration involved in CCM growth – activation of PI3 kinase – a target with existing drugs and with others under development. We will investigate the role of PI3 kinase in CCM lesion growth and its inhibition as a potential therapy. In parallel, we will search for somatic mutations in other genes that might enable repurposing of other existing drugs for CCM therapy. By capitalizing on our successes over the past four years, our renewal is designed to move from discovery, to mechanism, and then on to investigation of therapies for CCM disease.

## Key facts

- **NIH application ID:** 10022892
- **Project number:** 2P01NS092521-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Douglas A. Marchuk
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,353,471
- **Award type:** 2
- **Project period:** 2015-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022892

## Citation

> US National Institutes of Health, RePORTER application 10022892, Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis (2P01NS092521-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10022892. Licensed CC0.

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