# Investigating the Molecular Pathways of Cerebral Cavernous Malformation Maturation

> **NIH NIH F30** · DUKE UNIVERSITY · 2021 · $17,984

## Abstract

PROJECT SUMMARY: Cerebral cavernous malformations (CCMs) are dilated and hemorrhagic capillaries
that lose surrounding parenchymal cells and form multicavernous vascular lesions within the central nervous
system. Conservative estimates suggest that 300,000 people have this disease within the United States.
CCMs are caused by biallelic loss-of-function mutations within one of three different CCM genes and can occur
sporadically or through an autosomal-dominant mode of inheritance. When CCMs become symptomatic,
patients experience headache, seizure, focal neurologic deficits, recurrent hemorrhages, and stroke. No
pharmaceutical therapeutic is available to treat CCMs; the only therapy is surgical resection. Although curative,
these operations are invasive and limited by the anatomic location of the CCM; there is a large cohort of CCM
patients for whom no therapy is available. Decades of research have focused on two stages of the disease: 1)
the beginning - with in vitro and in vivo studies of CCM formation and 2) the end – with severely symptomatic
CCMs surgically resected from patients. What has eluded researchers is the ability to study CCM maturation
between formation and the development of symptoms. This limitation is due to the lack of an animal model that
can be induced to recapitulate the features of human CCMs and the lack of diversity within the human
samples, since only the most severe and symptomatic CCMs are resected – and only when absolutely
necessary. The clinically relevant CCM features are multicavernous structure, hemorrhaging, and inflammatory
infiltrate. The current inducible mouse model does not develop CCMs that hemorrhage or gain other important
pathologic features. The CCM research community needs a mouse model that better recapitulates the human
disease in order to gain greater insights into the disease course and begin to investigate the molecular
pathways necessary for CCM maturation. The overall objective of this proposal is to gain fundamental
knowledge of how CCMs mature and identify therapeutic interventions that disrupt CCM maturation and
improve disease outcomes. I have developed a variation of the inducible mouse model that results in a novel
phenotype of CCMs, dispersed throughout the brain, brainstem, and spinal cord, that develop and mature over
a period of several weeks. Unlike the traditional inducible model, my model develops a subset of CCMs that
hemorrhage and contain inflammatory infiltrates in the surrounding brain tissue. This model is a resource
that provides an opportunity to systematically investigate a previously unstudied component of the disease and
conduct the first studies to determine the role of specific molecular pathways in CCM maturation. Completion
of the following Specific Aims will generate fundamental knowledge of CCM pathology and advance the field
toward developing the first pharmacologic therapy for CCM patients:
Aim 1: Determine the order in which CCMs acquire pathologic features duri...

## Key facts

- **NIH application ID:** 10077346
- **Project number:** 5F30HL140871-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew Robert Detter
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $17,984
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077346

## Citation

> US National Institutes of Health, RePORTER application 10077346, Investigating the Molecular Pathways of Cerebral Cavernous Malformation Maturation (5F30HL140871-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077346. Licensed CC0.

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