This is a competing renewal program project grant application seeking support for resuming studies on the molecular events leading to the development of brain tumors. In the previous period of funding we utilized human neurotropic virus, JCV, to create experimental animals which developed tumors from external granular layer of the cerebellum modeling human medulloblastoma. In humans, medulloblastoma is the most common malignant brain tumor seen predominantly in children and is considered the prototypical embryonal neuroblastic neoplasm of the central nervous system (CNS). This program project, which is a confederation of three inter-related research projects with supporting scientific and administrative cores, each representing the natural evolution of the previously funded program, plans to launch a multidisciplinary approach utilizing experimental animals to decipher molecular events involved in the genesis of medulloblastoma. In Project #1, experiments are designed to investigate the regulation of gene expression involved in control of cell proliferation by the tumor suppressor protein, p53 and [g-catenin, a key component of the Wnt pathway which is involved in the oncogenesis and neurogenesis. By studying pl30/pRb2 pathway in Project #2, we will evaluate the the mechanism of regulation of this potent tumor suppressor and its well celebrated partner, p27 Kipl in medulloblastoma, determine the functional interaction of p130/pRb2 with JCV T-antigen, both in vitro and in pRb-knockout experimental animals. Finally, in Project #3, we will investigate the role of IGF-1 signal transduction pathway as our recent studies have provided compelling evidence for the involvement of major components of the IGF-1 receptor, IRS-1, which is induced by IGF-1 and triggers a cascade of cytoplasmid events involving AKT/PKB and MAP kinases in the development of medulloblastoma. These projects will be supported by the Experimental Animal Core (Core A) and the Neuropathology and Tissue Culture Core (Core B). The participants of this program project, who have worked synergistically to study CNS neoplasia, will convert the information from these molecular studies to translational research in devising therapeutic strategies toward brain tumors.
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