Improve understanding of the cell signaling events controlled by the three Cerebral Cavernous Malformation (CCM) proteins
Research Project by Chris Dibble
The goal of my research is to improve understanding of the cell signaling events controlled by the three Cerebral Cavernous Malformation (CCM) proteins. Mutation of any one of these proteins can result in development of Cerebral Cavernous Malformations, vascular lesions that can cause seizure, stroke, and focal neurological deficits. Currently, surgery or radiotherapy are the only treatment options, yet both are associated with significant risks and side effects. Thus, I hope to contribute towards development of a non-invasive pharmacological treatment for this disease. My work focuses on two main areas. The first is defining the important cytoskeletal signaling axis controlled by the CCM proteins. We recently showed that the CCM proteins regulate levels and activation of the small GTPase RhoA and its effector Rho kinase, and that loss of the CCM proteins results in a number of phenotypic and biochemical defects in endothelial cells. I hope to further define CCM regulation of the actin cytoskeleton in endothelial cells and find targets for pharmacological therapeutic intervention. My second focus is on characterizing CCM biology in the context of actual human patients. Thus far, all CCM research has been conducted with RNAi or in mouse models, each of which has limitations compared to cells from CCM mutation carriers. Using a novel technique, I am isolating and growing cells from human patients. This will allow, for the first time, the ability to accurately define the pathophysiology of CCM mutation in people affected by this prevalent and complex disease.