# Somatic mutation(s) and cellular changes in CCM pathogenesis

> **NIH NIH P01** · DUKE UNIVERSITY · 2021 · $331,316

## Abstract

ABSTRACT - PROJECT 1
Based on discoveries made in the previous cycle of our program project, Project 1 will probe deeply into
the cellular and molecular events of CCM pathogenesis. Using lineage tracing of murine CCM lesions
we showed that the initial event of lesion genesis is somatic loss of the remaining wild-type copy of the
Ccm gene, followed by a clonal expansion of endothelial cells harboring the same somatic mutation, and
what appears to be recruitment of additional ECs into the growing lesion – cells that do not harbor the
somatic mutation. Secondly, based on discoveries in the Kahn lab for a role for activated PI3 kinase in
lesion development in mouse CCM models, we identified activating PIK3CA mutations in more than 50%
of human CCM lesions. These collaborative discoveries suggest we have not yet fully understood the
molecular and cellular events that contribute to CCM lesion genesis, growth and maturation. In the first
Aim, we will deeply sequence bulk human CCMs to determine whether somatic mutation of any other
oncogenes contribute to the development of lesions. In a second Aim we will use single-cell genomic
DNA sequencing to determine whether individual endothelial cells require both the somatic CCM mutation
and the PIK3CA mutation (and/or mutation of other genes discovered in Aim 1), or instead whether these
genes are mutated in separate endothelial cell compartments of the lesion. In Aim 3, due to growing
evidence that the somatically mutated cells poison the non-mutant cells to recruit them into the growing
CCM, we will employ single-cell RNA sequencing to determine how the somatic mutation profile of the
lesional cell influences the cell’s gene expression profile. In addition to increasing fundamental
understanding of CCM pathogenesis, this work has therapeutic implications. The PI3K-AKT signaling
pathway is a target of existing drugs with others under development. Thus as part of this project we will
continue our quest for a highly effective therapy by testing compounds nominated in this or any of the
three projects, using our more clinically-relevant CCM mouse models developed in the past funding cycle.
With a more complete knowledge of the molecular and mutational signature of CCM lesional cells, we
hope to identify new targets for drug repurposing for CCM patients.

## Key facts

- **NIH application ID:** 10220145
- **Project number:** 5P01NS092521-07
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Douglas A. Marchuk
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,316
- **Award type:** 5
- **Project period:** 2015-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220145

## Citation

> US National Institutes of Health, RePORTER application 10220145, Somatic mutation(s) and cellular changes in CCM pathogenesis (5P01NS092521-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10220145. Licensed CC0.

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