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Cerebral Cavernous Malformations: From Two-Hit Mechanism to Developing a Targeted Therapy

dc.contributor.advisor Marchuk, Douglas A McDonald, David Andrew 2013-05-13T15:32:53Z 2014-05-08T04:30:05Z 2013
dc.description.abstract <p>Cerebral cavernous malformations (CCMs) are multicavernous vascular lesions affecting the central nervous system. Affected individuals have a lifetime risk of recurrent headaches, focal neurological deficits, seizures, and intracerebral hemorrhage leading to stroke. Patients tend to fall into two classes: familial cases with a known family history and multiple lesions, and; sporadic cases with no family history and single lesions. This epidemiological pattern suggests a two-hit mutational mechanism for CCM. While somatic mutations have been identified in lesions from familial patients, it is unknown if sporadic cases follow the same genetic mechanism. Using a next-generation sequencing strategy, I have identified somatic mutations from sporadic CCM lesions in the three known CCM genes, including one lesion bearing two independent mutations in CCM1. These data support a two-hit mutation mechanism in CCM for sporadic patients.</p><p>The mechanism of CCM pathogenesis (how mutations in one of the three CCM genes causes lesions to form and develop) is currently unknown. We developed mouse models that recapitulate the human disease. We have further shown that inhibition of Rho Kinase decreases the number of late-stage, multicavernous lesions. This is the first potential therapeutic strategy to specifically treat CCM, and suggests that the RhoA pathway is a central player in CCM pathogenesis.</p>
dc.subject Genetics
dc.subject Molecular biology
dc.subject Cerebral cavernous malformations
dc.subject Mouse
dc.subject RhoA
dc.subject Sequencing
dc.subject Somatic mutation
dc.title Cerebral Cavernous Malformations: From Two-Hit Mechanism to Developing a Targeted Therapy
dc.type Dissertation
dc.department Genetics and Genomics
duke.embargo.months 12

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