Vascular malformations such as cerebral cavernous malformations (CCMs) in the central nervous system predispose patients to headaches, seizures, focal neurogical deficit, and strokes. CCMs have a prevalence of 0.5% in the general population, but there are currently no effective medical techniques to prevent or treat their occurrence. Mutations in one of three genes have been linked with human familial CCMs. Our lab has identified two of those genes, CCM1 and CCM2, as regulators of RhoA/ROCK. With collaborators, the lab has developed a novel mouse model that mimics human CCM disease by abrogating Msh2 and Ccm1 function. The goal of this project is to understand how aberrant CCM1 signaling can lead to lesion formation and how different CCM1 signaling pathways are related. We hypothesize that CCM1 acts in a RhoA/ROCK-dependent and independent fashion in contributing to CCM lesion formation. To achieve our goal, we will determine how ROCK inhibition affects known CCM1 target pathways in vitro using primary endothelial cells and in vivo, utilizing the aforementioned mouse model for CCM lesion formation. Finally, we will study CCM1 signaling during normal development through the generation and characterization of Ccm1 conditional knockout mice. By understanding the relationship between different signaling events downstream of CCM proteins, we will reveal new potential therapeutic targets and form new insights that can aid in therapy development.

Public Health Relevance

CCM1 has recently been shown to regulate RhoA/ROCK activity; which implicates the RhoA/ROCK pathway in lesion development. While RhoA/ROCK-inhibiting pharmacological drugs are available and well-tolerated; there are presently no effective therapies to reduce the development or progression of cerebral cavernous malformations despite the fact that over 1 million Americans are affected by this disease. In clarifying the signaling hierarchy and level of ROCK-dependency involved in CCM pathogenesis; we will reveal information that can then be translated into developing additional or alternative therapies for treating CCM formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS084761-01
Application #
8594686
Study Section
Special Emphasis Panel (ZRG1-F01-F (20))
Program Officer
Koenig, James I
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
$49,214
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093