Abstract My lab has been the leader in the field of mouse modeling for brain tumors over the past 15 years. We have developed a suite of genetically engineered mouse models that are demonstrably representative of human gliomas and other tumor types. These models have been used to inform treatment options for clinical agents, and this now enables us to propose these models are suitable testbeds for testing potential major improvements to how these diseases are treated. We have three projects. 1) We are understanding the central role of specific splice variants of TrkB in embryonic development and oncogenesis throughout the body. The RCAS modeling system has been used here to show that forced expression of the embryonic splice variant in adult tissues leads to cancer formation broadly. In this project we will investigate the mechanisms of oncogenesis for this splice variant and determine if it could be a good diagnostic or therapeutic target. 2) We are now using the modeling system developed for glioma to address the biology of rare tumors driven by gene fusions. In this grant we propose to understand the mechanisms of oncogenesis for YAP1 gene fusions in the rare tumors ependymoma, porocarcinoma and aggressive meningioma (all for which we have YAP1 gene fusion driven models currently). 3) And, we will use these mouse models to study therapeutic response and identify therapeutic strategies for these fusion driven tumors including identification of FDA approved drugs that would intervene downstream of the action of the gene fusion.