David R. Lynch, MD, PhD

faculty photo
Professor of Neurology
Department: Neurology
Graduate Group Affiliations

Contact information
502 Abramson Center
Children's Hospital of Philadelphia
Philadelphia, PA 19104
Office: 2155902242
Fax: 2155903779
Lab: 2155901451
B.S. (Molecular Biophysics and Biochemistry)
Yale College, 1981.
M.D. (Neuroscience)
Johns Hopkins University, 1988.
Ph.D. (Neuroscience)
Johns Hopkins University, 1988.
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Description of Research Expertise

NMDA receptors

glutamate, receptor

Molecular biology

Excitotoxicity is a unique pathophysiological mechanism which is involved in cerebral ischemia, secondary damage in neuronal trauma, and neuronal damage from prolonged seizures. The deleterious effects from excitotoxicity result from calcium entry through a specific glutamate receptor, the N-methyl D-aspartate (NMDA) receptor. NMDA receptor antagonists act both as neuroprotective agents against excitotoxicity and as anticonvulsants in animals, but human clinical trials with the most potent agents have been complicated by side effects including psychosis. Much evidence indicates the presence of multiple types of NMDA receptors in the brain, and evidence from our laboratory suggests that different subtypes play different roles in physiological and excitotoxic processes. If one could develop therapeutic agents which are selective for the subtypes involved in excitotoxicity, one could more readily utilize NMDA receptor antagonists for treatment of human diseases.

We use a systematic approach to examine the subtype specific physiological and pharmacological properties of NMDA receptors. NMDA receptors are created in tissue culture expression systems, and their properties are studied biochemically, pharmacologically and physiologically to correlate receptor properties in these systems with such properties in vivo. We have previously shown that different NMDA receptor subtypes have distinct pharmacologies and produce different changes in intracellular calcium. In the near future we will extend these examinations of subtype specific properties to include the modulation of other intracellular messengers such as nitric oxide and examine the effect of such properties on excitotoxicity. Combined with our studies on the pharmacological specificity of NMDA receptor subtypes, this will facilitate the development of therapeutic agents directed to those NMDA receptors which play crucial roles in excitotoxicity.

Selected Publications

Lazaropoulos, M. Dong, Y., Clark,E.,Greeley, N. R.,Seyer, L.A., Brigatti,K. W., Christie, C., Perlman, S. L., Wilmot, G.R.,. Gomez, C. M. Mathews, K. D.,Yoon, G., Zesiewicz, T., Hoyle, C.,. Subramony, S.H., Brocht, A. F., Farmer, J. M., Wilson, R. B., Deutsch, E. C., Lynch, D. R. : Frataxin levels in peripheral tissue in Friedreich Ataxia. Annals of Clinical and Translational Neurology 2(8): 831-42. Aug 2015 Notes: in press.

Worth AJ, Basu SS, Deutsch EC, Hwang WT, Snyder NW, Lynch DR, Blair IA: Stable isotopes and LC-MS for monitoring metabolic disturbances in Friedreich's ataxia platelets. Bioanalysis 7(15): 1843-55, Aug 2015.

Seyer, L., Greeley, N., Foerster, D., Strawser, C., Gelbard, S., Dong, Y., Schadt, K., Cotticelli, M.G., Brocht, A., Farmer, J., Wilson, R.B., Lynch, D.R.: Open-label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol Scand. 2(1), Jul 2015.

Li, Y., Polak, U., Bhalla, A., Rozwadowska, N., Butler, J.S., Lynch, D.R., Dent, S.Y., Napierala, M.: Excision of expanded GAA repeats alleviates the molecular phenotype of Friedreich's ataxia. Molecular Therapy 23(6): 1055-65, Jun 2015.

Zyskind JW, Wang Y, Cho G, Ting JH, Kolson DL, Lynch DR, Jordan-Sciutto KL. : E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity. J Neurochem. 132(6): 742-55, Mar 2015.

C J Isaacs, J M Farmer1, K A Schadt, S Perlman, G R Wilmot, T Zesiewicz , C M Gomez, K D Mathews , C Hoyle , S H Subramony , G Obialisi, TAranca, C M Stephan, D R Lynch : Geographic and Socio-demographic Features of Friedreich Ataxia: Implications for Clinical Research. Journal of Rare Disease 2015 Notes: in press.

Li, Y. Lu, Y., Polak, U., Lin, K., Shen,J.,Farmer, J. Seyer, L., Bhalla1, A.D, Rozwadowska, N., Lynch, D.R.,Butler, J. S., Marek Napierala, M: Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus. Human Molecular Genetics 2015 Notes: in press.

Doss, S., Wandinger, K.-P., Hyman, B.T, Panzer, J., Synofzik, M., Dickerson, B., Mollenhauer, B., Scherzer, C., Ivinson, A., Finke, C., Schöls, L., Müller vom Hagen, J., Bittner, D., Priller, J., Spruth, E.,; Paul, F., Meisel, A., Lynch, D., Dirnagl, Q., Endres, M., Teegen, B., Probst, C; Komorowski, L., Stöcker, W., Dalmau, J., Prüss, H.: High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types. Annals of Clinical And Translational Neurology 1(10): 822-32, Oct 2014

Corben, L.A., Lynch, D., Pandolfo, M., Schulz, J.B., Delatycki, M.B.; Clinical Management Guidelines Writing Group. 2014 Dec;9(1):184. : Consensus Clinical Management Guidelines for Friedreich Ataxia Orphanet Journal of Rare Diseases 9(1): 184, doi: 10.1186/s13023-014-0184-7, December 2014.

Adang,L., Lynch, D. R., Panzer, J.: Pediatric anti-NMDA receptor encephalitis is seasonal. Annals of Clinical and Translational Neurology 1(11): 921-5, November 2014.

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Last updated: 11/16/2015
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