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Director, Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering
Institute for Cell Engineering
733 North Broadway St., Suite 711
Baltimore MD 21205
Molecular mechanisms of neuronal death and survival in models of stroke, Parkinson's and Alzheimer’s disease
Dr. Dawson’s laboratory is actively engaged in discovering and defining cell signaling pathways that lead to either neuronal survival or neuronal death. We have characterized neuronal injury and survival pathways in cell, fly and mouse models of Parkinson’s disease and stroke. She explores the role of the monogenic forms of Parkinson’s disease with a focus on parkin, EIF4G1 and LRRK2 in order to begin to define the biochemical signaling important to Parkinson’s disease. She has developed yeast, cellular, fly and mouse models to explore the Parkinson’s disease causing mutations as well as studying human neuronal cultures and human postmortem tissue to explore survival and disease signaling events relevant to Parkinson’s disease and stroke as well as to define neuron survival networks. Dr. Dawson’s laboratory in studying mechanisms of brain cell death in stroke, has defined the excitotoxic signaling pathway mediated by nitric oxide, poly(ADP-Ribose) polymerase and apoptosis inducing factor and named it Parthanatos, to distinguish it from other distinct forms of cell death including apoptosis, autophagy and necrosis. She has identified and characterized new survival molecules which include a transcription factor, NFIA, a novel E3 ligase, Iduna, a novel Notch regulatory protein, Botch, and a novel AAA+ ATPase, Thorase, that acts to disassemble the GRIP1/GluR2 complex, thus regulating excitability, plasticity and behavior, as well as a microRNA, mIR-223 that regulates neuronal survival, in part, through regulation of glutamate receptor expression. Recently we have found overlap between our investigations in Parthanatos and Parkinson’s disease in that age dependent loss of dopamine neurons due to expression of the parkin substrate, AIMP2, is dependent on Parthanatos. She is currently exploring if Parthanatos generally contributes to DA neurodegeneration and PD and has exciting new preliminary data that Parthantos is a common feature in many PD models as well as in human PD postmortem tissue. The Dawson laboratory employs advanced technologies in high throughput screening, next generation sequencing including RNA Seq and ChIP Seq, ribosomal foot printing, and high throughput proteomic analysis coupled with advanced computational biology to investigate signaling networks important in stroke, Parkinson’s disease and other neurodegenerative disorders. The overarching goal of the research is to understand death and survival signaling in order to identify new targets for therapeutic development.
Hong, S.J., H. Li, K.G. Becker, V.L. Dawson, and T.M. Dawson. Identification and Analysis of Plasticity-Induced Late Response Genes (PLINGS). Proc. Natl. Acad. Sci. U.S.A., 101:2145-2150 (2004)
Li, H., X. Gu, V.L. Dawson and T.M. Dawson. Identification of Calcium and Nitric Oxide Regulated Genes by Differential Analysis of Library Expression (DAzLE). Proc. Natl. Acad. Sci. U.S.A., 101: 647-652 (2004)
Chung K.K., B. Thomas, X. Li, O. Pletnikova, J.C. Troncoso, L. Marsh, V.L. Dawson and T.M. Dawson. S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin's Protective Function. Science 304(5675):1328-31 (2004)
Hong, S.J., T.M. Dawson and V.L. Dawson. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol. Sci. 25(5): 259-264 (2004)
Koh David W., Lawler Ann M., Poitras Marc F., Saski Masayuki, Wattler Sigrid, Nehls Michael C., Stoger Tobias, Porier Guy G., Dawson Valina L., Dawson Ted M. Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality. PNAS, 101: 17699-17704.
Yu Seong-Woon, Wang Hongmin, Poitras Marc F., Coombs Carmen, Bowers William J., Federoff Howard J., Poirer Guy G., Dawson Ted M., Dawson Valina. Mediation of Poly (ADP-Ribose) Polymerase-1-Dependant Cell Death by Apoptosis-Inducing Factor. Science, 297:259-263.
Wang, H., S.W. Yu, D.W. Koh, J. Lew, C. Coombs, W. Bowers, H.J. Federoff, G.G. Poirier, T.M. Dawson, and V.L. Dawson. “Apoptosis Inducing Factor (AIF) Substitutes for Caspase Executioners in N-methyl-D-aspartate Triggered Excitotoxic Neuronal Death.” J. Neurosci. 24: 10963-10973 (2004)
Koh, D.W., A.M. Lawler, M.F. Poitras, M. Sasaki, S. Wattler, M.C. Nehls, T. Stцger, G.G. Poirier, T.M. Dawson and V.L. Dawson. "Failure to Degrade Poly(ADP-ribose) Causes Increased Sensitivity to Cytotoxicity and Early Embryonic Lethality.” Proc. Natl. Acad. Sci. U.S.A. 101(51): 17699-17704 (2004)
David, K.K., M Sasaki, S.-W. Yu, T.M. Dawson and V.L. Dawson. “EndoG is Dispensable in Embryogenesis and Apoptosis,” Cell Death Diff. [Oct 21, 2005 Epub ahead of print] 13:1147–1155 (2006)
Yu, S.W., S.A. Andrabi, H. Wang, N.S. Kim, G.G. Poirier, V.L. Dawson and T.M. Dawson. “Apoptosis Inducing Factor (AIF) Mediates Poly (ADP-ribose) (PAR) Polymer Induced Cell Death” .” Proc. Natl. Acad. Sci. U.S.A. [Epub November 20, 2006, 10.1073/pnas.0606528103] (2006)
Anrabi, S., N.S. Kim, S.W. Yu, N.S. Kim, H. Wang, D. Koh, M. Sasaki, J.A. Klaus, T. Otsuka, Z. Zhang, R.C. Koehler, P. Hurn, G.G. Poirier, V.L. Dawson and T.M. Dawson. “Poly (ADP-ribose) (PAR) Polymer is a Novel Death Signal.” Proc. Natl. Acad. Sci. U.S.A. [Epub November 20, 2006, 10.1073/pnas.0606526103] (2006)
Haince JF, Kozlov S, Ouellet ME, Dawson VL, Dawson TM, Lavin MF, Poirier GG “Poly(ADP-ribosyl)ation is a potential modulator of DNA damage signaling.” East coast PARP 2006, Quebec Qc, Canada (2006)
Dawson, V.L., Zhikai Chi, Suk Jin Hong, Ho Chul Kang, Jianmin Zhang, Sika Zheng, and Ted M. Dawson. “Identification of New and Novel Survival Molecules Through Preconditioning.” The 26th Princeton Conference on Cerebrovascular Disease, Houston, Texas, 2008.