Cancer is a multistep disease involving a series of genetic alterations resulting in the loss of control of cell proliferation and differentiation. Such genetic alterations could emerge from the activation of oncogenes and the loss or malfunctioning of tumor suppressor gene activity. Our understanding of cancer has been greatly increased by using DNA tumor viruses and their transforming proteins as a biological tool for deciphering a cascade of events which lead to deregulation of cell proliferation and thus, tumor formation. For the past ten years, the Program Director has focused on studies of the molecular biology of the human neurotropic papovavirus, JCV. This virus causes a fatal neurodegenerative disease of the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. JCV is a common human virus infecting greater than 80% of humans with no obvious clinical symptoms. Moreover, in recent years, the increased incidence of acquired immune deficiency syndrome (AIDS) and use of immunosuppressive chemotherapy have dramatically increased the incidence of PML. The coincident occurrence of malignant astrocytes and oligodendrocytes in PML patients, coupled with the induction of glioblastoma in JCV-infected non-human primates provides intriguing speculation on the association between JCV and CNS malignancies. The oncogenicity of JCV in promoting neural tumors has been well-established in several experimental animals. Intracerebral inoculation of JCV into neonatal hamsters results in a high percentage (70%) of animals with brain tumors including glioblastomas. This program project entitled """"""""Viral model for tumor pathogenesis in brain"""""""" utilizes a magnificent model of JCV-induced brain tumors in a multidisciplinary approach to: (i) investigate the molecular circuits involving cytokines such as TGFb and cell cycle regulatory proteins, i.e., the E2F family, in development of brain tumors; (ii) evaluate the biological significance of the Rb tumor suppressor protein family with a great emphasis on pRb2/p130 and associated kinases in virally induced brain tumors in hamster, in parallel with brain tumors from human; (iii) evaluate the potential of brain tumors to serve as immunologic targets and assess the level of immunoregulators including MHC antigen and cytokines such as TGFb and TNFa in these tumors. The three highly integrated, yet independent projects will adhere to each other and be supported by two scientific cores which will characterize tumors and tumor cells by MRI and perform neurohistopathological analysis of cells and tissue. The correlative MRI-histopathology studies by the cores will provide a unique opportunity to conduct molecular biological studies during the course of tumor formation in a well-controlled manner. This program project brings together basic and clinical scientists from the Departments of Biochemistry and Molecular Biology, Microbiology and Immunology, Neurology, Neurosurgery, Pathology, Anatomy and Cell Biology, and Radiology to perform the proposed studies.
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