This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Background: Medulloblastoma is the most common childhood brain tumor and is of scientific interest because tumors are essentially overgrowths of perinatal neuronal stem cells in the external granular layer of the cerebellum. Medulloblastomas arise in the cerebellum early in childhood, coincident with the development of the cerebellum, which occurs after birth by the proliferation and differentiation of the cells in the external granular layer (EGL) of the cerebellum. This project addresses the biochemical underpinnings of medulloblastoma through a genetically engineered mouse model (GEM), developed by the Keller laboratory. Rationale: In their recent publication, the Keller laboratory has uncovered a new mechanism of disease progression for medulloblastoma, as well as a clinically-available drug that halts and reverses tumor growth. They have shown that bortezomib (velcade, PS-341), a 26S proteasome inhibitor, had significant anti-tumor activity in medulloblastoma, which was accompanied by restoration of Ptc1 protein (from the second, non-mutated allele) and downregulation of the hedgehog signaling pathway. This work represents an ongoing strategy of reverse genetics in the mouse as a way of determining the contribution of a single gene to a complex biological process, such as developmental patterning. Questions: This DBP poses several important challenges for the CIBC: (1) Establishing a pipeline for segmenting the cerebellum of the mice;(2) Addressing the more general problem of complex shape with relatively high-curvature features that present variations important to the analysis;and (3) Performing a significant amount of 3D visualization. Design &Methods: The project design consists of three essentials aims: (1) Quantify macroscopic, morphological changes in the 21-day preneoplastic (pretumor) phase for the medulloblastomaprone mice;(2) Characterize tumor shape and invasiveness of established medulloblastomas as they develop in the first six weeks of life;and (3) Develop a shape-based biomarker to quantify the therapeutic efficacy and mechanisms of bortezomib on medulloblastomas.
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