David R. Lynch, MD, PhD
Professor of Neurology
Department: Neurology
Graduate Group Affiliations
Contact information
502 Abramson Center
Children's Hospital of Philadelphia
Philadelphia, PA 19104
Children's Hospital of Philadelphia
Philadelphia, PA 19104
Office: 2155902242
Fax: 2155903779
Fax: 2155903779
Email:
LYNCHD@mail.MED.UPENN.EDU
LYNCHD@mail.MED.UPENN.EDU
Links
Neuroscience graduate group faculty webpage.
Pharmacological Sciences graduate group faculty webpage.
Neuroscience graduate group faculty webpage.
Pharmacological Sciences graduate group faculty webpage.
Education:
B.S. (Molecular Biophysics and Biochemistry)
Yale College, 1981.
Ph.D. (Neuroscience)
Johns Hopkins University, 1988.
M.D. (Neuroscience)
Johns Hopkins University, 1988.
Permanent linkB.S. (Molecular Biophysics and Biochemistry)
Yale College, 1981.
Ph.D. (Neuroscience)
Johns Hopkins University, 1988.
M.D. (Neuroscience)
Johns Hopkins University, 1988.
Description of Research Expertise
RESEARCH INTERESTSNMDA receptors
KEY WORDS:
glutamate, receptor
RESEARCH TECHNIQUES
Molecular biology
RESEARCH SUMMARY
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
Heather L. Plasterer, Eric C. Deutsch, Matthew Belmonte, Elizabeth Egan, David R. Lynch, and James R. Rusche.: Development of Frataxin Gene Expression Measures for the Evaluation of Experimental Treatments in Friedreich's Ataxia. PLOS one 2013 Notes: (in press)LA Seyer, Dr Lynch: Analysis of the visual system in Friedreich ataxia Journal of Neurology 2013 Notes: in press.
Regner, S.R., Lagedrost, S.J., Plappert, T., Paulsen, E.K., Friedman, L.S., Snyder, M.L., Perlman, S.L., Mathews, K.D., Wilmot, G.R., Schadt, K.A., Sutton, M.S., Lynch, D.R.: Analysis of Echocardiograms in a Large Heterogeneous Cohort of Patients With Friedreich Ataxia. American Journal of Cardiology 109(3): 401-5, Feb 2012
Meier, T., Perlman, S. L., Rummey, C., Coppard, N. J., Lynch, D.R.: Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. Journal of Neurology 259(2): 284-91, Feb 2012
Gleichman., A.J, Spruce, L.A., Dalmau, J., Seeholzer, S.H., Lynch, D.R.: Anti-NMDA Receptor Encephalitis Antibody Binding Is Dependent on Amino Acid Identity of a Small Region within the GluN1 Amino Terminal Domain. Journal of Neuroscience 32(32): 11082-94, August 2012.
Lynch, DR, Willi, SM, Wilson,RB, Cotticelli, MG, Brigatti, K, Deutsch, EC , Kucheruk, O, Shrader, W., Rioux, P, Miller, G, Hawi, A, Sciascia, T: A0001 in Friedreich ataxia: Biochemical characterization and effects in a clinical trial. Movement Disorders 27(8): 1026-33, July 2012.
Mahishi, L., Lynch, D.R., Ratan, R.: MiR-886-3p levels are elevated in Friedreich ataxia. Journal of Neuroscience 32(27): 9369-73. July 2012.
Evans-Galea, M.V., Carrodus, N., Rowley, S.M., Corben, L.A., Tai, G., Saffery, R., Galati, J., Wong, N.C., Craig, J.M., Lynch, D.R., Regner, S., Brocht, A.F.D., Perlman, S.L., Bushara, K.O., Gomez, C.M., Wilmot, G.R., Li, L., Varley, E., Delatycki, M.B., Sarsero, J.P..: FXN methylation predicts expression and clinical outcome in Friedreich ataxia. Annals of Neurology 71(4): 487-97, April 2012.
Singh, P., Doshi, S., Spaethling, J.M., Hockenberry, A.J., Patel, T.P., Geddes-Klein, D.M., Lynch, D.R., Meaney, D.F. : NMDA receptor mechanosensitivity is governed by the C-terminus of the NR2B subunit. Journal of Biological Chemistry 287(6): 4348-59, Feb 2012.
Hsien-Yang, L., Yong, H., Bruneau, N.,Roll, P., Roberson, E., Hermann, M.,Quinn, E., Maas, J., Edwards, R., Ashizawa, T., Baykan, B., Bhatia, K., Bressman, S., Bruno, M. K., Brunt, E. R., Caraballo, R., Echenne, B., Fejerman, N., Frucht, S., Gurnett, C. A., Hirsch, E., Houlden, H., Jankovic, J., Lee, W. L., Lynch, D. R., Mohamed, S., Müller, U., Nespeca, M. P., Renner, D., Rochette, J., Rudolf, G., Saiki, S., Soong, B.W., Swoboda, K. J., Tucker, S., Wood, N., Hanna, M., Bowcock, A., Szepetowski, P., Fu, Y.H., Ptacek, L.: Mutations in the novel protein PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Reports 1(1): 2-12, January 2012.