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Translational Neurobiology Laboratory
Faculty Director: Wenzhen Duan, M.D, Ph.D.
The goals of the laboratory of Translational Neurobiology are: (1) understand the pathogenesis and cell death pathways in neurodegenerative disorders to reveal potential therapeutic targets for pharmaceutical intervention; (2) investigate endogenous survival pathways and try to induce these pathways to restore full function or replace lost neurons; and (3) identify biomarkers to mark disease progression and evaluate therapeutics.
Figure legend. Tet-off inducible PC12 cell model of PD. E46K mutant alpha-synuclein was inducibly expressed in PC12 cells when doxycycline (Dox) was withdrawal from culture medium. Green color represents living cells with dye calcein AM, red color represents dead cells with dye ethidium homodimer-2, and blue color represents nucleus by DNA dye Hoechst 33342. Note cell death is increased in cells expressing E46K mutant alpha-synuclein.
The research projects in the laboratory focus on models of Huntington's disease(HD) and Parkinson's disease (PD). We use a combination of cell biology and transgenic animal models of these diseases. The current research projects are: (1) identifying and validating targets for therapeutic intervention; (2) identifying and stimulating endogenous survival pathway to restore neuronal function; (3) screening and discovering new potent neuroprotective compounds in cell models of HD and PD; (4) preclinical trials of new candidate compounds in transgenic mouse models of HD and PD; and (5) developing and validating biomarkers to mark disease progression and evaluate therapeutics. These projects are supported by NINDS and the High Q foundation.
The laboratory welcomes undergraduates, graduate students, and postdoctoral fellows who are interested in our research.
Figure legend: Representative in vivo MRI images with deformation-based morphometry (DBM) of relative tissue volume; major structural boundaries defined in the control mouse are overlaid on the R6/2 mouse and color-coded Jacobian maps for visual guidance. In the Jacobian map, only regions with significant change in local tissue volume (false discovery rate = 0.05) are shown. The color reflects the normalized local tissue volume with respect to local tissue volume in similar regions in the control mouse brains. Green and blue in the Jacobian map indicate mild and severe atrophy, respectively. Atrophy in the neocortex (white arrows), striatum (yellow arrows), piriform cortex (magenta arrows), hippocampus (red arrows), thalamus (orange arrows), and amygdala (cyan arrows) can be appreciated (Zhang et al., Neuroimage 2010 49(3):2340-51).
Mali Jiang, M.D., Ph.D., Postdoctoral Fellow
Yong Cheng, Ph.D. Postdoctoral Fellow
Naoki Masuda, M.D., Postdoctoral Fellow
Lan Xiang, Ph.D. Postdoctoral Fellow
Jiawei Wang, M.D., Ph.D. Postdoctoral Fellow
Qi Peng, Research Specialist
Jinrong Fu, Ph.D., Postdoctoral Fellow
Jing Jin, M.D., Postdoctoral Fellow
Duan W, Zhang Z, Gash DM, Mattson MP. Participation of Prostate Apoptosis Response-4 in Degeneration of Dopaminergic Neurons in Models of Parkinson's Disease. Ann Neurol, 1999; 46:587-597.
Duan W, Zhu X, Ladenheim B, Yu QS, Guo ZH, Olyer J,Cutler RG, Cadet JL, Greig NH and Mattson MP . Synthetic p53 Inhibitors Preserve Dopaminergic Neurons and Motor Function in Experimental Parkinsonism. Ann Neurol 2002 ; 52:597-606.
Duan W, Guo ZH, Jiang HY, Ware M, Li XJ, Mattson MP. Dietary Restriction Normalizes Glucose Metabolism and BDNF Levels, Slows Disease Progression and Increases Survival in Huntingtin Mutant Mice. Proc. Natl. Acad. Sci. U S A 2003 Mar 4;100(5):2911-6.
Duan W, Guo ZH, Jiang H, Ware M, Mattson MP. Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology 2003, Jun;144(6):2446-53.
Duan W, Guo Z, Jiang H, Ladenheim B, Xu X, Cadet JL, Mattson MP. Paroxetine retards disease onset and progression in Huntingtin mutant mice. Ann Neurol 2004, 55(4):590-4.
Wang W, Duan W, Igarashi S, Morita H, Nakamura M, Ross CA. Compounds blocking mutant huntingtin toxicity identified using a Hunington's disease neuronal cell model. Neurobio of Dis, 2005, 20(2):500-8.
Sredni B, Geffen-Aricha R, Duan W, Albeck M, Shalit F, Lander HM, Kinor N, Sagi O, Albeck A, Yosef S, Brodsky M, Sredni-Kenigsbuch D, Sonino T, Longo DL, Mattson Ddagger 1 MP, Yadid G. Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models. FASEB J. 2007 21(8):1870-83.
Duan W, Peng Q, Masuda N, Ford E, Tryggestad E, Ladenheim B, Zhao M, Cadet JL, Wong J, Ross CA. Sertraline Slows Disease Progression and Increases Neurogenesis in N171-82Q mouse model of Huntington's Disease. Neurobio Dis, 2008;30: 312-322.
Zhang J, Peng Q, Li Q, Jahanshad N, Hou Z, Jiang M, Masuda N, Langbehn DR, Miller MI, Mori S, Ross CA, Duan W. Longitudinal characterization of brain atrophy of a Huntington's disease mouse model by automated morphological analyses of magnetic resonance images. Neuroimage, 2010, 49(3):2340-51.
Jiang M, Porat-Shliom Y, Pei Z, Cheng Y, Xiang L, Sommers K, Li Q, Gillardon F, Hengerer B, Berlinicke C, Smith WW, Zack D, Poirier MA, Ross CA, Duan W. Baicalein reduces E46K alpha-synuclein aggregation in vitro and protects cells against E46K alpha-synuclein toxicity in cell models of familiar Parkinsonism. J Neurochem, 2010, 114(2):419-29.
The projects in the lab are performed in close collaboration with Dr. Christopher A. Ross within Division of Neurobiology, Dr. Susumu Mori and Dr. Jiangyang Zhang in the Department of Radiology at Hopkins, Dr. Mark P. Mattson in National Institute on Aging.