David R. Lynch, MD, PhD

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Professor of Neurology
Department: Neurology

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.
Ph.D. (Neuroscience)
Johns Hopkins University, 1988.
M.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

Rojsajjakul, Teerapat; Wu, Linfeng; Grady, Connor; Hwang, Wei-Ting; Mesaros, Clementina; Lynch, David; Blair, Ian: Liquid Chromatography-Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich’s Ataxia. Analytical Chemistry 2023 Notes: in press.

Jamison Seabury, Spencer Rosero, Anika Varma, Jennifer Weinstein, Charlotte Engebrecht, Nuran Dilek, John Heatwole, Danae Alexandrou, Brittany Cohen, Jane Larkindale, David R. Lynch, Courtney Park, Sub Subramony, Ellen Wagner, Susan Walther, Mckenzie Wells, Christine Zizzi, and Chad Heatwole: The Friedreich's Ataxia-Health Index (FA-HI): Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure. Neurology Clinical Practice 2023 Notes: in press.

Rodden, L, McIntyre, K, Keita, M, Park, C, Wells, Profeta, V, Waldman, A., Rummey, C, Balcer, L.: Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia. Annals of Clinical Translational Neurology 2023.

Lam, C., Gilliam, K., Rodden, L., Schadt, K., Lynch, D.R. Bidichandani, S.: FXN gene methylation determines carrier status in Friedreich ataxia. J Med Genet 2023 Notes: in press.

Vizcarra, J A , Paul, R A, Hamedani, A G, Lynch, D, Aamodt, W W: Clinical Reasoning: A 48-Year-Old Man with Spasticity and Progressive Ataxia Neurology 2023 Notes: in press.

Rodden, L. N., Rummey, C., Kessler, S., Wilson, R. B., Lynch, D. R.: A novel metric for predicting severity of disease features in Friedreich ataxia. Movement Dis 2023 Notes: in press.

Lynch, D.R., Mathews, K. D., Perlman, S., Zesiewicz, T., Subramony, S, Omidvar, O., Vogel, A. P., Krtolica, A., Litterman, N., van der Ploeg, L., Heerinckx, F., Milner, P., Midei M.: Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia Journal of Neurology 2023 Notes: in press.

Rodden, L. N., Rummey, C., Dong, Y. N., Lagedrost, S., Regner, S., Brocht, A., Bushara, K., Delatycki, M. B., Gomez, C. M., Mathews, K., Murray, S., Perlman, S. L., Ravina, B., Subramony, S. H., Wilmot, G. Zesiewicz, T., Bolotta, A., Domissy, A., Jespersen, C., Ji, B., Soragni, E., Gottesfeld, J. M., Lynch, D. R.: A non-synonymous SNP in SIRT6 predicts neurological severity in Friedreich ataxia. Frontiers in Molecular Biosciences 9: 933788, Sep 2022

Wang, D., Ho, E. S., Cotticelli, M. G., Xu, P., Napierala, J. S., Hauser, L. A., Napierala, M., Himes, B. E., Wilson, R. B. , Lynch, D. R., Mesaros, C.: Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia. J Lipid Res 63(9): 100255, Sep 2022

Rummey, C., Corben, L. A., Delatycki, M., Wilmot, G., Subramony. S. H., Corti, M., Bushara, K., Duquette, A., Gomez, C., Hoyle, J. C., Roxburgh, R., Seeberger, L., Yoon, G., Mathews, K., Zesiewicz. T., Perlman, S., Lynch, D. R.: Natural History of Friedreich's Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design. Neurology 99(14): e1499-510. Jul 2022

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Last updated: 06/02/2023
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