CHARACTERIZATION OF THE CELLULAR FUNCTIONS OF Krit1, THE DISEASE GENE RESPONSIBLE FOR TYPE 1 CEREBRAL CAVERNOUS MALFORMATIONS (CCM1)

Cerebral cavernous malformations (CCMs; 116860) are vascular malformations that may involve any part of the central nervous system and are characterized by abnormally enlarged and leaky capillary cavities (caverns) that predispose to epileptic attacks, neurological deficits, or intracerebral hemorrhage. Their surgical removal is necessary for patients with recurrent hemorrhage or intractable seizures, given that direct pharmacological treatments are not available so far. Magnetic resonance imaging (MRI) is the diagnostic modality of choice. CCMs have been estimated to affect from 0.1 to 0.5% of the general population, although only 20-30% of affected individuals develop symptomatic disease; this typically begins in the third through fifth decades of life, although lesions have been described in all age groups with no sex predominance. These vascular malformations are a disease of proven genetic origin. At least 47% of the hereditary forms of CCMs are caused by mutation in the KRIT1 gene (also called CCM1) (604214). However, neither the CCM1 pathogenesis mechanisms nor the physiological functions of the KRIT1 protein are understood so far. To engage in this important research challenge we will perform molecular and cellular studies aimed at defining the cellular function of KRIT1, as well as the molecular mechanisms that are affected by mutation of the KRIT1 gene. In particular, we will test our major hypothesis that KRIT1 plays a role in the regulation of cell adhesion processes linked to the dynamic remodeling of the blood vessels. To reach this objective, we will take also advantage of our ongoing collaboration with a research group with specific expertise on molecular analyses of angiogenesis. The outcomes of this research could help to build up a comprehensive model of the pathogenesis of this genetic disease, thus providing a framework for future development of novel therapeutic strategies.