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dc.contributor.advisor Yan, Hai en_US
dc.contributor.author Reitman, Zachary J. en_US
dc.date.accessioned 2012-05-25T20:07:53Z
dc.date.issued 2012 en_US
dc.identifier.uri http://hdl.handle.net/10161/5418
dc.description Dissertation en_US
dc.description.abstract <p>Gliomas are tumors of the central nervous system for which improvements in treatment are critically needed. Mutations in IDH1 and IDH2, which encode the cytosolic and mitochondrial NADP+-dependent isocitrate dehydrogenases, respectively, are frequent in gliomas. Here, we summarize recent literature concerning gliomas, the normal cellular functions of IDH1/2, the epidemiology of IDH1/2 mutations, and the understanding of the function of IDH1/2 mutations in cancer. We then show in vitro using liquid chromatography-mass spectrometry that a function of many IDH1/2 mutations is to produce 2-hydroxyglutarate. Next, we use a mass spectrometry based platform to characterize metabolic changes in a glioma cell line expressing IDH1/2 mutants and show that the IDH mutants are associated with lowered N-acetylated amino acids both in this cell line model and in primary tumor tissue. Finally, we develop and characterize a Drosophila melanogaster (fruit fly) model of IDH1/2-mutated cancer by expressing the mutated Drosophila homolog of IDH1 in fly tissues using the UAS-Gal4 binary expression system. These results delineate downstream molecular players that likely play a role in IDH1/2-mutated cancer and provide a model organism for interrogation of genetic networks that interact with IDH1/2 mutation. These findings refine our understanding of glioma pathogenesis and may inform the design of new glioma therapies.</p> en_US
dc.subject Cellular biology en_US
dc.subject Genetics en_US
dc.subject Molecular biology en_US
dc.subject 2-hydroxyglutarate en_US
dc.subject Drosophila en_US
dc.subject IDH1 en_US
dc.subject IDH2 en_US
dc.subject Metabolomics en_US
dc.subject N-acetyl-aspartyl-glutamate en_US
dc.title Genetic Dissection of the Biological and Molecular Role of IDH1 Mutations in Glioma en_US
dc.type Dissertation en_US
dc.department Pathology en_US
duke.embargo.months 48 en_US
duke.embargo.release 2016-05-15

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