Project description:Cerebral cavernous malformations are vascular anomalies that can cause hemorrhagic stroke. Mutations in genes encoding Krit 1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) proteins cause CCM. A loss in teh expression of any of these CCM proteins disrupts normal cerebral vessel development by disrupting the cytoskeleton and thereby inhibits endothelial tube ofrmation. Examination of cellular changes based on the loss of CCM gene expression may lead to the methods for early detection and prevention of CCM associated hemorrhagic stroke.
2014-06-09 | PXD000362 | Pride
Project description:Somatic variants of MAP3K3 are sufficient to cause cerebral cavernous malformations
Project description:Loss-of-function variants in CCM3/PDCD10 predispose to cerebral cavernous malformations (CCMs) that are vascular lesion of the central nervous system. Using CRISPR/Cas9 genome editing and RNA sequencing, we have shown that long-term inactivation of CCM3 in human endothelial cells dysregulates fibronectin expression and thus impairs the assembly of a functional fibronectin matrix by endothelial cells.
Project description:CCM3 regulates blood-brain-barrier integrity and vascular maturation in vivo. CCM3 loss-of-function variants predispose to cerebral cavernous malformations (CCM). Various signalling pathways are deregulated upon CCM3 depletion in endothelial cells (ECs). In this study, we established a crRNA:tracrRNA:Cas9 RNP approach to efficiently knockout CCM3 in human ECs and studied the molecular and functional effects of its long-term inactivation. Using small RNA sequencing, we show that CCM3 regulates the expression of aging‑associated miRNAs.
