Cerebral Cavernous Malformation (CCM) is a hereditary stroke syndrome that has no treatment other than neurosurgery. Loss of one of three genes causes CCM. By reducing the expression of one of these genes (CCM2) in the cells that line blood vessels (endothelial cells), unique structural and functional phenotypes result. We will use a chemical suppression screen in cell culture systems to discover small molecules that rescue these distinct phenotypes. Our high-throughput platform consists of two primary screens: the first is an imaging screen with machine-learning based phenotype analysis;the second screen uses electric cell substrate impedance sensing to detect changes in endothelial barrier function. We will then further screen the top candidate compounds in a mouse model of human CCM disease. The result of this project will be personalized medicine candidates for the treatment of CCM caused by mutations in the CCM2 gene.

Public Health Relevance

Cerebral Cavernous Malformation (CCM) is a hereditary stroke syndrome that has no treatment other than neurosurgery. We will use a chemical suppressor screen to identify potential therapeutics for treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080893-02
Application #
8731282
Study Section
Special Emphasis Panel (ZRG1-BST-U (55))
Program Officer
Jett, David A
Project Start
2013-09-15
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$322,678
Indirect Cost
$106,116
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99