# RhoA Signaling and Stroke

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2020 · $439,028

## Abstract

Hemorrhagic stroke accounts for ~13% of all stroke cases. One of the main underlying cases of this type of
stroke is the rupture of intracranial aneurysm (IA), with consequent subarachnoid hemorrhage and critically
reduced blood flow downstream of the affected vessel. A recent study of both familial and sporadic IA cases
identified mutations in the ArhGEF17 gene as associated with increased risk for IA in both European and Asian
populations. ArhGEF17 codes for a Dbl-family GEF (guanine nucleotide exchange factor) specific for RhoA. The
molecular architecture of ArhGEF17 is unusual for a Dbl-family GEF, in that it is predicted to harbor an unusual
split PH-domain (sPH) downstream of the DH domain, and a predicted β-propeller (WD40) domain. Interestingly,
the human genome has two homologues of ArhGEF17 with this architecture: ArhGEF10 and GRINCH-GEF
(ArhGEF10L) (see Fig 1). A polymorphism in the ArhGEF10L gene has also been associated with increased risk
to ischemic stroke. The structures of these three proteins are not known, and the specific functions of the
putative sPH and WD40 domains are not understood.
 We propose an exploratory project aimed at structural and functional characterization of ArhGEF17/10. We
will characterize the structural features of the ArhGEF17/10 family, with the overarching goal to gain
understanding of the structure-function relationships in these proteins. Our ultimate objective is to gain detailed
understanding of the structure and functions of the three globular domains, and to determine if and how are the
GEFs regulated by the supramodular architecture. Focusing on the physiological function of ArhGEF17, we
want to determine if it regulates cerebral vascular tone, by down regulating its expression in smooth muscle in
mouse mid cerebral arteries, and in endothelial cells, using adenoviral shRNAs. RhoA activity and vasodilation
will be monitored under basal conditions and in response to increases in intraluminal pressure and agonists in
the arteries. Membrane resistance measurements in endothelial cells will monitor changes in permeability. This
will lay the ground work for the future development of a conditional ArhGEF17 knockout mouse to determine
whether deletion of ArhGEF17 in either smooth muscle or endothelial cells (or both) leads to increased cerebral
vessel dilation and/or increased endothelial permeability, and increases the propensity for cerebral hemorrhage.

## Key facts

- **NIH application ID:** 10058968
- **Project number:** 1R21NS118647-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Zygmunt S Derewenda
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,028
- **Award type:** 1
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058968

## Citation

> US National Institutes of Health, RePORTER application 10058968, RhoA Signaling and Stroke (1R21NS118647-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10058968. Licensed CC0.

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