Modeling and Characterizing Idh Mutant Gliomas in Drosophil melanogaster (2013 -
Marla Tipping, Providence College
Abstract:Gliomas are the most
common and lethal form of brain tumor. In an effort to better understand
the biology of these rapidly proliferating, aggressively invasive, and
highly treatment resistant tumors Drosophila models have been
established. The successful recapitulation of the human glioma phenotype
through increased receptor tyrosine kinase (RTK) activity suggests the
fly glia as a promising model for the study of these tumors. Recently
genes encoding the metabolic enzymes Isocitrate dehydrogenase 1 (IDH1)
and 2 (IDH2) were found to be mutated in up to 70% of low-grade and
medium grade gliomas, and in 15-20% of adult acute leukemia samples.
These findings were the first to link the IDH gene to tumorigenesis.
IDH1 and IDH2 function as metabolic enzymes to irreversibly catalyze the
oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG),
however little is known about the metabolic impact on tissues harboring
IDH mutant proteins. This proposal aims to model the IDH mutant
phenotype in Drosophila glial cells to characterize their metabolic
status, and elucidate changes in the IDH protein interaction network.
These goals will be achieved by 1) careful analysis of altered
proliferation and cellular metabolism in Drosophila Idh1 mutant larval
glia, and 2) identification of proteins interacting with Idh1 wild type
and Idh1 mutant proteins. Results of this study of mutant IDH function
in gliomas will increase our ability to better treat these aggressive
tumors at the level of cellular metabolisms.