Understanding the mechanism for MEK-dependent growth in pediatric low-grade gliomas
Mentor Name: David Gutmann
Children with NF1 are at an increased risk of developing low-grade gliomas of the optic nerve and brainstem. While not typically fatal, these low-grade gliomas (LGGs) can cause life-long morbidity. NF1-LGGs are characterized by increased MAPK activation, similar to that seen in LGGs arising in children without NF1-harboring KIAA1549: BRAF and FGFR1 genomic alterations. For this reason, current therapies are focused on drugs that suppress MAPK activation (MEK inhibitors). Using LGG models in mice, analysis has revealed that MAPK activation results in an increased expression of IRX2 and NPTX1; our current project seeks to determine how IRX2 and NPTX1 control MEK-dependent LGG growth. First, we will determine whether IRX2 and/or NPTX1 silencing abrogates NF1-deficient and KIAA1549: BRAF-expressing LGG growth using short hairpin RNA (shRNAi) targeting. Then, we will determine whether IRX2 and NPTX1 regulate each other’s expression using real time quantitative PCR (qPCR) and Western blotting as well as explore the possibility that IRX2 and NPTX1 converge on the same signaling pathway.
