# Downstream molecular mechanisms underlying cerebral cavernous malformation

> **NIH NIH P01** · DUKE UNIVERSITY · 2021 · $314,670

## Abstract

SUMMARY – PROJECT 3
Recent studies by our group and others have identified MEKK3-KLF2/4 signaling as the
direct target of CCM complex function, and showed that loss of CCM function confers
lesion formation through gain of MEKK3 signaling and elevated KLF2 and KLF4
expression in brain endothelial cells. Unexpectedly, we have also found that endothelial
TLR4 activation by lipopolysaccharide derived from gram negative bacteria in the gut
microbiome plays a central, upstream role in the activation of MEKK3-KLF2/4 signaling
and CCM formation in both mice and humans. These findings have culminated in a now
widely accepted model of CCM disease, but the downstream effectors by which KLF2
and KLF4 drive lesion formation remain unknown. Our preliminary studies reveal two
new insights into the downstream events that drive CCM formation: 1) PI3K gain of
function synergizes with CCM loss of function to drive lesion formation in mice and a
majority of surgically resected human CCM lesions, and 2) ADAMTS cleavage of peri-
vascular versican drives the CCM phenotype in mice. Project 3 will define the roles of
PI3K signaling and versican proteolysis during CCM pathogenesis using established and
newly developed mouse genetic models. These studies will strongly complement those
in Project 1 and Core A that examine the PIK3CA mutations in human CCM lesions and
a cell non-autonomous mechanism by which wild-type endothelial cells contribute to
CCM lesions. Most importantly, we expect these studies to be rapidly translated to the
clinic by providing support for the use of FDA-approved agents such as the PI3K
pathway inhibitor rapamycin to treat CCM disease.

## Key facts

- **NIH application ID:** 10220147
- **Project number:** 5P01NS092521-07
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** MARK L KAHN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $314,670
- **Award type:** 5
- **Project period:** 2015-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220147

## Citation

> US National Institutes of Health, RePORTER application 10220147, Downstream molecular mechanisms underlying cerebral cavernous malformation (5P01NS092521-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10220147. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*