PROJECT SUMMARY High grade gliomas (pHGGs) represent the greatest number of solid tumors in the pediatric population, and now are the greatest cancer related cause of death. Within the past 20 years, treatment progress has remained stagnant, as 5-year survival rates remain less than 20%. Ras signaling has been shown to be highly upregulated in many pHGGs, although Ras mutations are very rare. The role of negative regulators of Ras signaling, Ras GAPs, in pHGGs remain vastly understudied. We discovered that Neurofibromin 1 (Nf1) is a Ras GAP commonly mutated in 10% or higher of pHGGs. Additionally, 1 in 3000 individuals per year are born with Neurofibromatosis Type I, a tumor predisposition syndrome with somatic heterozygous NF1 mutation. These individuals are at greater risk for developing a number of cancers, including brain tumors. We leveraged pHGG transcriptomic and proteomic datasets and GSEA pathway analysis and identified that alterations in cellular metabolism correlate with NF1 loss in pediatric high grade gliomas, specifically through vast changes in lipid content. I hypothesize that NF1 is a critical regulator of lipid metabolism, and that metabolic intervention could be used to treat NF1 driven gliomas. My goal during the remainder of my graduate training (F99 phase) is to elucidate how NF1 loss alters fatty acid/lipid metabolism, and whether targeting this phenotype in pHGG models is efficacious. Upon finishing my graduate training, I will identify a post-doctoral mentor (K00) and further investigate the metabolic roles of NF1 on brain tumor epigenetics. The proposed project leverages in vitro and in vivo systems to study a distinct metabolic phenotype at the cellular and tumor levels. Our research will inform a molecular mechanism and translational relevance for a role of NF1 in lipid metabolism. This data could also be applicable to other cancer types and tumor predisposition syndromes. Combined together, the two phases of this award will provide me with the means to establish myself as a successful cancer researcher and enable me to lay the foundation for my own independent cancer research laboratory predicated on intertwined study of brain tumor biology, neuroscience, and metabolism.