Neuroimmunology of Degenerative Diseases
Principal Investigator: Terrence Town, PhD
It was once thought that cells of the immune system were excluded from the central nervous system due to the existence of a blood-brain-barrier, which separates circulating cells from brain cells. This so-called brain "immune privilege" was the dominant view for decades. However, within the last 15 years, it has become increasingly clear that immune cells frequently enter and survey the brain milieu, giving rise to the field of neuroimmunology. What's more, the laboratory and others have shown that key immune molecules such as CD40, CD40 ligand, tumor necrosis factor-alpha, and transforming growth factor-beta play central roles in the pathoetiology of neurodegenerative diseases such as Alzheimer's disease, encephalitis, stroke, and multiple sclerosis. The laboratory uses genetically modified mice (transgenics and knock-outs) programmed to develop these diseases as pre-clinical models to conduct laboratory studies aimed at targeting such neuroimmune molecules for eventual therapeutic intervention. We rely heavily on cutting edge visual analyses of brain pathology and cellular/molecular biological techniques to accomplish this goal. Included in these techniques are ELISA, quantitative real-time PCR, molecular cloning, Western blot, Northern blot, Southern blot, and bright-field, fluorescence, transmission electron, and confocal microscopy. This work, funded by the National Institutes of Health and the Alzheimer's Association, has led to numerous publications in peer-reviewed journals, some of which appear in Journal of Immunology, Immunity, Journal of Neuroscience, Science, Nature, Nature Medicine, Nature Neuroscience, and Proceedings of the National Academy of Sciences USA.
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Recent Publications
1. Wang T*, TOWN T*, Alexopoulou L*, Anderson JF, Fikrig E, Flavell RA. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis (2004). Nature Medicine, 10:1366-1373. *First author equivalent contribution.
2. Spilianakis CG, Lalioti M*, TOWN T*, Lee GR, Flavell RA. I, Interchromosomal associations between alternatively expressed loci (2005). Nature (article), 435:637-645. *These authors contributed equally to this work.
3. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, TOWN T, Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces amyloidosis in Alzheimer transgenic mice (2005). Journal of Neuroscience, 25:8807-8814.
4. TOWN T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via Toll-like receptor 3 (2006). Journal of Immunology, 176:3804-3812.
5. Obregon D, Rezai-Zadeh K, Sun N, Bai Y, Hou H, Zeng J, Mori T, Shytle D, TOWN T, Tan J. ADAM10 activation is required for green tea EGCG-induced alpha-secretase cleavage of amyloid precursor protein (2006). Journal of Biological Chemistry, 281:16419-16427.
6. Nikolic V, Bai Y, Obregon D, Hou H, Zeng J, Ehrhart J, Mori T, Shytle D, TOWN T*, Tan J*. Transcutaneous Abeta immunization of Alzheimers' mice reduces cerebral amyloidosis in the absence of T-cell infiltration or microhemorrhage (2007). PNAS, 104:2507-2512. *corresponding authors.
7. TOWN T, Breunig JJ, Sarkisian MR, Spilianakis C, Ayoub AE, Liu X, Ferrandino AF, Gallagher AR, Li MO, Rakic P, Flavell RA. The stumpy gene is required for mamallian ciliogenesis (2008). PNAS, 105:2853-2858.
8. TOWN T*, Lauoar Y, Pittenger C, Mori T, Tan J, Duman R, Flavell RA*. Blocking TGF-β innate immune signaling mitigates Alzheimer-like pathology in transgenic mice (2008). Nature Medicine, 14:681-687. *corresponding authors.
9. Laouar Y, TOWN T, Jeng D, Wan Y, Tran E, Kuchroo VJ, Flavell RA. TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis (2008). PNAS, 105:10865-10870.
10. Mori T, Tan J, Arendash GW, Koyama N, Nojima Y, TOWN T. Overexpression of Human S100B Exacerbates Brain Damage and Peri-infarct gliosis after permanent focal ischemia (2008). Stroke, 39:2114-2121.
11. Breunig JJ, Sarkisian M, Arellano JI, Morozov YM, Ayoub AE, Wang B, Flavell RA, Rakic P, TOWN T. Primary cilia regulate postnatal neurogenesis by mediating sonic hedgehog signaling (2008). PNAS, 105:13127-13132.
12. TOWN T, Bai F, Wang T, Kaplan A, Flavell RA, Fikrig E. Tlr7 mitigates lethal West Nile encephalitis by affecting IL-23-dependent immune cell infiltration and homing (2009). Immunity, 30:242-253.
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