JC virus (JCV) is the causative agent of the human CNS demyelinating disease progressive multifocal leukoencephalopathy (PML). The mechanism by which demyelination occurs in the presence of this ubiquitous virus is not fully understood. However, PML occurs under conditions of immunosuppression, which permits the virus to undergo a lytic cycle of replication. The lytic cycle of JCV is initiated specifically in glial cells through transcription of the JCV early gene for the viral T- antigen. Prior studies of transgenic CD1 mice that express this gene and its promoter have shown that JCV T-antigen expression has led to a variable degree of CNS dysmyelination in a dose-dependent fashion. In vitro data from our laboratory demonstrate a dose-dependent trans-acting suppression of myelin basic protein (MBP) promoter activity by the T- antigen, suggesting that JCV early gene product expression may play a crucial role in regulating the expression of myelin gene products and thus lead to demyelination.
the aim of this project is to determine the impact of JCV T-antigen on the development and maintenance of CNS myelin. the original line of JCV T-antigen CD1 transgenic mice is now available for study in our laboratory. However, an additional transgenic line will be developed to examine, in depth, viral-induced dysmyelination in whole animal system that resembles JCV-induced PML in immunosuppressed humans. The experimental design includes: (i) analysis of myelin formation and expression of myelin genes, i.e. myelin basic protein, at the transcriptional and post-transcriptional levels in T-antigen-producing transgenic lines during brain development; (ii) identification of the cis-acting element responsive to the T-antigen that is located in the MBP 5' upstream sequence, and identification of the cellular factor(s) that interacts with the cis-acting sequences and trans-suppresses the MBP promoter; (iii) examination of the biological function of the T-antigen- target sequence in suppressing the MBP promoter in tissue culture and in a whole animal system, and genetic manipulation of a transgenic line containing a multimerized copy of the target to impair interaction of the trans-suppressor protein with the endogenous MBP promoter. The information obtained from these experiments should enhance our understanding of the pathogenesis of PML and provide clues regarding the development of demyelinating disease at the molecular level.
| Rom, Slava; Rom, Inna; Passiatore, Giovanni et al. (2010) CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells. FASEB J 24:2292-300 |
| Piña-Oviedo, Sergio; Khalili, Kamel; Del Valle, Luis (2009) Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of progressive multifocal leukoencephalopathy. Acta Neuropathol 118:235-47 |
| Sariyer, Ilker K; Safak, Mahmut; Gordon, Jennifer et al. (2009) Generation and characterization of JCV permissive hybrid cell lines. J Virol Methods 159:122-6 |
| White, Martyn K; Johnson, Edward M; Khalili, Kamel (2009) Multiple roles for Puralpha in cellular and viral regulation. Cell Cycle 8:1-7 |
| 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 |
| Mukerjee, Ruma; Deshmane, Satish L; Fan, Shongshan et al. (2008) Involvement of the p53 and p73 transcription factors in neuroAIDS. Cell Cycle 7:2682-90 |
| Fischer-Smith, Tracy; Bell, Christie; Croul, Sidney et al. (2008) Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies. J Neurovirol 14:318-26 |
| Khalili, Kamel; Sariyer, Ilker Kudret; Safak, Mahmut (2008) Small tumor antigen of polyomaviruses: role in viral life cycle and cell transformation. J Cell Physiol 215:309-19 |
| Kaminski, Rafal; Darbinyan, Armine; Merabova, Nana et al. (2008) Protective role of Puralpha to cisplatin. Cancer Biol Ther 7:1926-35 |
| 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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