THE ROLE OF BHLH GENES IN GLIOGENESIS AND GLIOMA BIOLOGY

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This proposal outlines a set of experiments designed to explore the relationship between the expression and function of basic helix-loop-helix (bHLH) transcription factors in normal and transformed glial cells. The proteins transcribed by bHLH genes regulate developmental programs in many cell types, such as neurons and muscle, and are expressed in tumors of the corresponding lineages. Their expression in tumors has been shown to be of significance for diagnosis-and prognosis and understanding mechanisms of defective cell-cycle control. Glial tumors are largely incurable because their cells are capable of unregulated proliferation and migration in the brain. Glial progenitor cells differentiate, proliferate and migrate in the brain, but in a controlled fashion. It is not known how these normal control mechanisms are deregulated in glial tumor cells. The study of glial progenitor cell biology, and its translation to glioma cell biology, is hampered by a lack of understanding of specific genes that control glial cell development, proliferation and migration. Unlike other cell types, the expression of bHLHs genes in glia, glial specific genes have not been reported. This proposal will i) characterize the expression patterns of known bHLH genes in glia and gliomas, li) identify and clone glial specific bHLH genes, and iii) perform functional assays to determine the effects of bHLH gene expression on glial progenitor and tumor cell differentiation, migration and proliferation. The central hypothesis of this proposal is that deregulated bHLH function contributes to glial tumor phenotype by promoting, or failing to control, tumor cell migration, differentiation, and proliferation. It is expected that these studies will offer powerful tools for the continued study of glial and glioma biology, and translate into improved clinical management of glioma patients by providing better diagnostic and prognostic markers and potential targets for novel therapies.