Cerebral cavernous malformations (CCM) are vascular abnormalities in the brain which cause migraines seizures, and hemorrhagic stroke. Recently, mutations in the RAP1A-interacting gene CCM1 (KRIT1) have been identified in dominant inherited CCM type1. We will develop an animal model of CCM by targeted mutation of the mouse Ccm1 gene. Insertion of a LacZ reporter gene in the Ccm1 locus will allow us to investigate the developmental and cell-specific expression pattern of CCm1. Using heterozygous mutant mice, we will test the """"""""two-hit"""""""" hypothesis of lesion formation which predicts that the vascular malformation in heterozygous human patients are due to somatic mutation resulting in complete loss of CCM1 at the site of the lesion. The phenotype of homozygous mutant mice will illuminate unidentified functions of Ccm1 during vasculogenesis or development of other organs. Fibroblast cells cultured from mutant mice will be used to investigate the role of Ccm1 in cell proliferation a Rapla signaling pathways. These experiments will help to explain the formation of CCM in human patients and shed light on basic aspects of vascular morphology and development.
