This application proposes to investigate the activation of primary olfactory bulb neurons and neuroblastoma cells by a cytokine, interleukin 12 (IL-12). This will explore a new area of the interaction between the immune system and the CNS. IL-12 acts at the cusp between the innate and the specific immune response development in the periphery, activating natural killer cells and promoting the differentiation of CD4+ Th1 lymphocytes. Preliminary data provide compelling evidence that there is an IL-12 receptor expressed by neurons, both in vitro and in vivo. Additional data are provided which show that IL-12 treatment leads to induction of the IL-12 receptor and nitric oxide synthase type 1 (NOS-1) leading to the development of an antiviral state in neurons both in vitro and in vivo, promoting recovery and survival from VSV encephalitis. The studies included in this application will 1) use cellular and molecular approaches to characterize the IL-12 receptor of neurons, determine the ontogeny of expression, and if IL-1 2R is internalized with ligand binding; 2) examine the signal transduction pathway for similarities and differences with the pathway described in Th1 Lymphocytes; calcium mobilization, and translocation of NF-kB complexes will be explored; 3) analyze genes induced by IL-I2 treatment of neurons by examination of specific candidates. This work will lead to a greater understanding of the complex and intimate interactions between the immune system and the central nervous system.
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| Tsvetkov, Andrey S; Ando, D Michael; Finkbeiner, Steven (2013) Longitudinal imaging and analysis of neurons expressing polyglutamine-expanded proteins. Methods Mol Biol 1017:1-20 |
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| Reiss, Carol Shoshkes (2010) Cannabinoids and Viral Infections. Pharmaceuticals (Basel) 3:1873-1886 |
| D'Agostino, Paul M; Reiss, Carol Shoshkes (2010) A confocal and electron microscopic comparison of interferon beta-induced changes in vesicular stomatitis virus infection of neuroblastoma and nonneuronal cells. DNA Cell Biol 29:103-20 |
| Tsvetkov, Andrey S; Miller, Jason; Arrasate, Montserrat et al. (2010) A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A 107:16982-7 |
| Miller, James M; Bidula, Sarah McNulty; Jensen, Troels Mygind et al. (2010) Vesicular stomatitis virus modified with single chain IL-23 exhibits oncolytic activity against tumor cells in vitro and in vivo. Int J Interferon Cytokine Mediat Res 2010:63-72 |
| D'agostino, Paul M; Amenta, Jessica J; Reiss, Carol Shoshkes (2009) IFN-beta-induced alteration of VSV protein phosphorylation in neuronal cells. Viral Immunol 22:353-69 |
| Miller, James; Bidula, Sarah M; Jensen, Troels M et al. (2009) Cytokine-modified VSV is attenuated for neural pathology, but is both highly immunogenic and oncolytic. Int J Interferon Cytokine Mediat Res 1:15-32 |
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