Glioblastoma multiforme (GBM) are by far the most common tumor of the central nervous system and continue to be associated with a dismal prognosis. Although our understanding of genetic and biochemical changes accompanying glial cell malignancy has improved in recent years, few studies have examined the impact and mechanisms responsible for aberrant changes in RNA splicing. Because previous studies have demonstrated the aberrant RNA splicing of numerous genes associated with GBM, this is a promising new area for therapeutic development. We have focused on the fibroblast growth factor receptor 1 gene (FGFR1) because the level of a high-affinity form of FGFR1 is dramatically elevated in GBM as a result of altered expression and RNA splicing. We have linked the aberrant splicing FGFR1 RNA to a dramatic upregulation in the expression of the multifunctional RNA-binding protein, known as polypyrimidine tract binding protein (PTB). This observation led to the hypothesis that GBM-associated alterations in normal RNA splicing, including but not limited to FGFR1, act to facilitate either initiation or growth of glial tumor either initiation or growth. We propose the following Specific Aims: (1) to define the role of the FGFR1 D1-loop (included by normal splicing) in receptor signaling, (2) to confirm a functional role of aberrant FGFR1 splicing in glial cell malignancy, (3) to confirm a requirement for PTB expression in glial cell malignancy and define the specific targets of PTB action, (4) to develop a mouse model for PTB- mediated oncogenesis.
Aims 1 - 3 will employ new experimental tools that allow for the specific correction of aberrant RNA splicing, the targeted ablation of gene products, and the application of genome-wide exon expression profiling.
Aim 4 will employ proven transgenic approaches to establish astrocyte-specific expression of PTB. The resulting data will show whether alterations in FGFR1 RNA splicing or PTB trans-acting factor expression play a role in glial cell malignancy. A better understanding of this process may shed light on the transformation of astrocytes and provide new targets for suppressing their malignant growth.
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