The clinical focus of this research is medulloblastoma (MB), a malignant brain tumor that arises in the cerebellum in children. The main limitation to current therapy is collateral damage to the developing brain by anti-cancer agents. Insights into new treatments that interfere with tumor cell growth without impeding neural development will come from an increased understanding of the basic biology of MB. The overall objective of this research is to use a genetically defined, mouse model of MB, which we created using the RCAS/tv-a system, to identify key signaling proteins in MB formation. This system utilizes a retroviral vector (RCAS), derived from avian leukosis virus, subgroup A (ALV-A), and a transgenic mouse line (Ntv-a) that expresses TVA (the receptor for ALV-A) under control of the nestin gene promoter. The nestin gene encodes an intermediate filament protein expressed by neural progenitor cells prior to their commitment to neuronal or glial differentiation. This makes it possible to target expression of exogenous genes specifically to nestin-expressing neural progenitors in the cerebellum - the cells-of-origin for MB.
Specific aim 1 is to generate in vivo mouse models of MB by using the RCAS/tv-a system to transfer combinations of genes that stimulate proliferation, block differentiation, and inhibit apoptosis in neural progenitor cells.
Specific aim 2 is to establish cell lines from MBs generated by RCAS-mediated gene transfer. Using these cell lines, we will pharmacologically block the individual signaling pathways activated by retroviral gene transfer in order to assess the relative contribution of proliferation, differentiation, and apoptosis to tumor growth. The results of this study will provide insights into signal transduction pathways that promote MB growth. This information can be used to identify molecular therapeutic targets and facilitate development of preclinical testing models for chemotherapeutic agents.
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