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dc.contributor.advisorHowell, Brian
dc.contributor.authorMansaray-Storms, Zainab Y.
dc.date.accessioned2021-07-19T13:04:11Z
dc.date.available2021-07-19T13:04:11Z
dc.date.issued2016
dc.identifier.urihttp://hdl.handle.net/20.500.12648/1888
dc.description.abstractCerebral cavernous malformation 3 (CCM3) is one of three genes which when mutated plays a role in the neurovascular disease, cerebral cavernous malformation. Through a number of diverse binding partners, CCM3 plays a critical role in modulating several processes including cell survival, migration and vascular development. However, how CCM3 regulates many of these pathways remains unclear. An interaction with Stk25, a serine/threonine kinase with roles in cell polarity suggests CCM3 might play a role in the functions of Stk25. Here we characterize a role for CCM3 in cellular polarity. We identify a function for CCM3 in epithelial polarity through its association with and regulation of the conserved LKB1 signaling pathway. We find that CCM3 associates with STRADα, the regulatory pseudokinase of the LKB1 complex, and is necessary for LKB1-mediated cell polarization. To determine whether this novel association of CCM3 with STRADα and LKB1 pathway plays a role in CCM3-phenotype in endothelial cells, we analyzed the gene expression profiles of endothelial cells deficient in CCM3 protein. We identified changes in gene expression induced by CCM3 knockdown, particularly a significant downregulation in expression of cell adhesion molecules, a dysregulation of extracellular matrix signaling and an activation of p53 signaling pathway. This work defines a novel regulatory role for CCM3 in epithelial cell polarity and provides preliminary insights into downstream signaling pathways affected by the reduction of CCM3 in endothelial cells with potential impact in CCM disease pathogenesis.en_US
dc.language.isoen_USen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectUNDERSTANDINGen_US
dc.subjectCELLULARen_US
dc.subjectMOLECULARen_US
dc.subjectMECHANISMSen_US
dc.subjectCEREBRALen_US
dc.subjectCAVERNOUSen_US
dc.subjectMALFORMATION 3 (CCM3)en_US
dc.titleUNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS OF CEREBRAL CAVERNOUS MALFORMATION 3 (CCM3)en_US
dc.typeDissertationen_US
dc.description.versionNAen_US
refterms.dateFOA2021-07-19T13:04:11Z
dc.description.institutionUpstate Medical Universityen_US
dc.description.departmentNeuroscience and Physiologyen_US
dc.description.degreelevelPhDen_US
dc.identifier.oclc1034990740


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Attribution-NonCommercial-NoDerivatives 4.0 International
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