Author

Aimee Two

Date of Award

8-2-2010

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Dr. Murat Gunel

Second Advisor

Dr. Angeliki Louvi

Abstract

IN VIVO ANALYSIS OF CCM3, A GENE INVOLVED IN CEREBRAL CAVERNOUS MALFORMATION DEVELOPMENT. Aimee Two, Angeliki Louvi, and Murat Gunel. Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT. Cerebral cavernous malformations (CCMs), one of the most common vascular malformations of the central nervous system (CNS), occur due to both sporadic and familial mutations in any of the three CCM genes: CCM1, or KRIT1; CCM2, or malcavernin; and CCM3, the Programmed Cell Death 10 gene. As the most recently discovered of these genes, CCM3 remains poorly understood. In vitro analysis has suggested a role for it in apoptosis, but in vivo studies of this gene are limited and thus are the goal of the current work. Using conditional knockout mice in which Ccm3 has been inactivated in neural cells, experimental animals were created that develop lesions resembling human CCMs. In situ hybridization and immunohistochemistry were used to compare staining patterns of glial fibrillary acidic protein (GFAP) and vimentin, both expressed in astrocytes, with vimentin being expressed specifically in activated astrocytes, as well as connexin43, a gap junction protein that links astrocytic foot processes along the blood brain barrier (BBB), and aquaporin 4, a water channel expressed exclusively in astrocytes, between control and experimental brains. Results showed an increase in GFAP and vimentin expression in experimental brains, suggesting increased glial activation, but a decrease in that of connexin43 and aquaporin 4, suggesting an abnormality of these astrocytes. Given that CCMs represent endothelial cell and not astrocyte pathology, these results suggest that lesion formation may be related to disrupted communication within the neurovascular unit.

Comments

This is an Open Access Thesis.

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