# CCM3-mediated exocytosis in pathogenesis of cerebral cavernous malformation

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $464,146

## Abstract

CCM3 is one of mutated genes responsible for the human CCM disease, a pathological condition
that affects the vasculature of the central nervous system and results in stroke, seizure and
cerebral hemorrhage with a high prevalence. CCM consists of dilated and multiple capillary
channels formed by a single layer of endothelium, lacking all other normal vessel wall elements.
Patients with inherited autosomal dominant CCM carry loss of function mutations in one of three
genes: CCM1, CCM2 and CCM3. Deletion in one of the three Ccm genes in vascular EC induces
CCM lesions in mice. However, it is unknown why both humans and mice with CCM3 loss exhibit
more severe phenotype than those with loss of CCM1 or CCM2. Our unexpected discovery of the
involvement of CCM3 in EC exocytosis, prompt us to hypothesize that alteration in
CCM3-regulated EC exocytosis contributes to the pathogenesis of the CCM disease. We propose
the following two specific aims: 1) To determine the role of CCM3-regulated brain EC exocytosis in
CCM disease phenotypes. We will establish mouse CCM models even closer to human CCM
disease by creating brain EC-specific Ccm3 deletion, and determine therapeutic effects of Angpt2
neutralization antibodies in the new CCM3 mouse models. 2) To explore crosstalk of
CCM3-mediated EC exocytosis with other pathways implicated in CCM formation. We will test if
inhibition of exocytosis in ECs blocks RhoA-dependent EC stress fiber formation,
TGF-β/Smad/BMP-mediated EndMT signaling, and MEKK3-ERK5-KLF4-mediated matrix
remodeling. Conversely, test if gain- or loss-of-function of RhoA, TGF-β and MEKK3-ERK5-KLF4
signaling regulate EC exocytosis. In summary, the complementary approaches using genetic, cell
biological and imaging analyses will facilitate our understanding of the molecular mechanisms and
pathogenesis involved in acquisition of cerebral cavernous malformations, and help in defining new
and more effective therapies. Our findings should benefit the general understanding of the
regulatory mechanisms of exocytosis, which also occurs in other cardiovascular cells and ECs of
other cardiovascular organs such as heart, lung and aortae. Therefore, our present study is of
broad significance in cardiovascular research.

## Key facts

- **NIH application ID:** 9867743
- **Project number:** 5R01HL136507-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** DAVID F STERN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $464,146
- **Award type:** 5
- **Project period:** 2017-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867743

## Citation

> US National Institutes of Health, RePORTER application 9867743, CCM3-mediated exocytosis in pathogenesis of cerebral cavernous malformation (5R01HL136507-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9867743. Licensed CC0.

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