Our overall goal in this proposal is to elucidate the role of Trk receptor signaling in the pediatric brain tumor medulloblastoma. Recent work by our laboratory, and by other investigators, demonstrates that medulloblastoma cells transfected with TrkA receptors undergo apoptosis when stimulated with NGF. This observation is remarkable and biologically important, because in all other cells studied, including other types of tumor cells, Trk receptor activation promotes differentiation (or proliferation) and survival. We hypothesize that activation of endogenous TrkA, TrkB and TrkC receptors causes medulloblastoma cells to die, and that activation of Trk receptors inhibits the growth, viability and spread of medulloblastoma cells in vivo. Our studies will address these hypotheses by using primary medulloblastoma cells cultured from patient tumor samples, and by analyzing the effects of Trk receptor activation both in vitro and in vivo in a xenograft model. We hypothesize that Trk receptor-mediated apoptosis requires a conflict between Trk receptor-activated signaling pathways and over-expression of c-myc in order to kill medulloblastoma cells. We will test this hypothesis by examining the Trk receptor-mediated signaling pathways that are required for apoptosis and by inhibiting (or further over-expressing) c-myc to determine its effect on apoptosis. Because Trk receptor status is the molecular feature that is most clearly associated with survival in medulloblastoma patients, understanding the role of Trk receptor signaling in medulloblastoma has important clinical and therapeutic implications. By incorporating studies on primary medulloblastoma tumor cells that are derived from patient samples, and that express endogenous Trk receptors, for both in vitro and in vivo studies, this proposal is designed to determine the biological role for Trk receptor signaling in medulloblastoma. Dr. Paul Mischel is a board certified neuropathologist, and has done a period of initial molecular neuroscience training with Dr. Louis F. Reichardt at HHMI-UCSF. He proposes a structured career development/training plan that will enable him to develop the skills necessary to become a leading independent investigator. He has chosen Dr. Harvey Herschman as the primary mentor, and Drs. William C. Mobley and Louis F. Reichardt as co- mentors. This team of internationally recognized mentors is committed to helping Dr. Mischel meet all of the aims of this proposal, and to ensure that he develops into an outstanding independent investigator.
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