A Subependymal Giant Cell Astrocytoma (SEGA) Mouse Model

The overall goal of the research proposed is to test the hypothesis that Tsc2 deletion in SVZ NSCs hyperactivates mTOR and elevates translation of mRNAs that generates a stochastic unstable stem-like state which can be stabilized with mTOR inhibitors or retinoic acid. This grant seeks to generate, characterize, and test therapeutic compounds a novel mouse model of Tuberous Sclerosis Complex (TSC). The TSC model produces mice having abnormal neuron migration, neuron morphology, hyperactivation of the mTORC1 pathway and most notably, the previously elusive subependymal giant cell astrocytoma (SEGA). The grant will help generate a better understanding of how SEGAs form and when and to test the extent that SEGAs can be permanently pharmacologically ablated. The grant will help address two TSCRP focus areas. First, this grant will help us to gain a deeper knowledge of TSC signaling pathways and the cellular consequences of TSC deficiency by examining molecular pathways and translational abnormalities in TSC SEGA cells. Second, this grant will test and facilitate therapeutics, biomarker, and clinical trials research. We will study a new class of third generation mTORC1 inhibitors tethered to rapamycin which are exemplified by the compound RapaLink1. We will determine the extent that RapaLink1 permanently reduces SEGA size and frequency. We will simultaneously study an FDA approved molecule called all-trans retinoic acid (ATRA). This annual report highlights research progress over the first period.