Determining the hierarchy of signaling pathways regulated by the CCM1 protein

University Of California, San Diego, La Jolla CA

Investigators

Abstract

DESCRIPTION (provided by applicant): 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.