Date of Award

7-9-2009

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Murat Gunel

Abstract

Cerebral cavernous malformations (CCM) are a central nervous system vascular malformation often responsible for hemorrhagic strokes. Molecular genetic studies have identified three genes (CCMl KRITI, CCM2 Malcavernin, and CCM3 PDCDIO) and four possible loci responsible for the pathogenesis of these lesions. CCMl functions through integrin signaling and regulation of RACl activity and may be involved in the MAPK and JNK signaling cascades. We hypothesized that CCM2 likely functioned through the same pathways and that CCM3 expression is regulated by these stress-induced signaling cascades. We showed that CCM2 likely functions through the MAPK pathway as the mouse homolog, osmosensing scaffold protein for MEKK3 (OSM), has been shown to interact in the p38 mitogen activated protein kinase (p38 MAPK) signaling pathway regulated by RAC1. We confirmed that CCMl and CCM2 signal as a complex since co-immunoprecipitation indicates joint expression. We also characterized the role of CCM3 in the MAPK pathway by identifying interacting serine threonine kinases (STK) and KIAA0826 based on yeast two-hybrid data. This was further examined through immunohistochemical analysis showing CCM3 is expressed in a variety of human organs especially arterial vascular endothelium in a similar pattern to CCM2. The yeast two-hybrid data supports current theories that there is a link between CCM pathogenesis and the ERK-MAPK cascade. These findings correlate with previous studies and further elucidate the signaling pathways involved in CCM pathogenesis which may in turn be helpful in future therapeutic advances.

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