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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Fountain, Jane W
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Temple University
Schools of Arts and Sciences
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Johnson, Edward M; Daniel, Dianne C; Gordon, Jennifer (2013) The pur protein family: genetic and structural features in development and disease. J Cell Physiol 228:930-7
Riolfi, Mirko; Ferla, Rita; Del Valle, Luis et al. (2010) Leptin and its receptor are overexpressed in brain tumors and correlate with the degree of malignancy. Brain Pathol 20:481-9
Urbanska, Katarzyna; Pannizzo, Paola; Lassak, Adam et al. (2009) Estrogen receptor beta-mediated nuclear interaction between IRS-1 and Rad51 inhibits homologous recombination directed DNA repair in medulloblastoma. J Cell Physiol 219:392-401
Gualco, Elisa; Wang, Jin Ying; Del Valle, Luis et al. (2009) IGF-IR in neuroprotection and brain tumors. Front Biosci (Landmark Ed) 14:352-75
Rossi, Alessandra; Russo, Giuseppe; Puca, Andrew et al. (2009) The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells. Int J Cancer 125:235-43
Urbanska, Katarzyna; Pannizzo, Paola; Grabacka, Maja et al. (2008) Activation of PPARalpha inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines. Int J Cancer 123:1015-24
Brown, Meghan C; Staniszewska, Izabela; Del Valle, Luis et al. (2008) Angiostatic activity of obtustatin as alpha1beta1 integrin inhibitor in experimental melanoma growth. Int J Cancer 123:2195-203
Brown, Meghan C; Staniszewska, Izabela; Lazarovici, Philip et al. (2008) Regulatory effect of nerve growth factor in alpha9beta1 integrin-dependent progression of glioblastoma. Neuro Oncol 10:968-80
Del Valle, Luis; White, Martyn K; Khalili, Kamel (2008) Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 67:729-40
Perez-Liz, Georgina; Del Valle, Luis; Gentilella, Antonio et al. (2008) Detection of JC virus DNA fragments but not proteins in normal brain tissue. Ann Neurol 64:379-87

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