Unravelling the role of the Polycomb Group Protein BMI1 in Cerebral Cavernous Malformations

Cerebral cavernous malformation (CCM) is a rare genetic disease characterized by enlarged blood vessels mainly forming within the brain. These malformed vessels are fragile and prone to rupture causing hemorrhagic events plus a variety of neurological symptoms that severely affect life quality and survival of CCM patients. At the moment, there is no effective medical treatment to prevent and/or regress the symptoms: the only available therapy is surgical resection of the lesions, not often applicable due to the inaccessibility of the lesions in some areas of the brain. CCM disease is caused by loss of function mutations in anyone of three distinct genes, CCM1, CCM2 and CCM3. The cell type mostly affected by such mutations is the endothelium that forms the internal cover of cerebral blood vessels and faces blood. In previous work, we and others have found that ECs that line vascular lesions show an abnormal functioning and resemble a vascular tumor. In this project, we plan to elucidate the dysfunctional role played by the Polycomb Group protein, BMI1, in the context of CCM disease and evaluate the mechanisms resolved upon the inhibition of such altered activity. The potential outcome of this project is the definition of the activity and safe use of one or more compounds to be tested in clinical trials on CCM patients. The goal of finding a cure to a rare genetic disease is relevant to Telethon foundation’s mission.