David R. Lynch, MD, PhD

faculty photo
Professor of Neurology
Department: Neurology

Contact information
502 Abramson Center
Children's Hospital of Philadelphia
Philadelphia, PA 19104
Office: 2155902242
Fax: 2155903779
Lab: 2155901451
Education:
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

RESEARCH INTERESTS
NMDA 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

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

Dong, Y. N., Mesaros, C., Xu, P., Mercado-Ayón, E., Halawani, S., Ngaba, L. V., Warren, N., Sleiman, P., Rodden, L. N., Schadt, K. A., Blair, I. A., Lynch, D. R. : Frataxin controls ketone body metabolism through regulation of OXCT1. PNAS Nexus 1(3): pgac142. Jul 2022

Jamison Seabury, Danae Alexandrou, Nuran Dilek, Brittany Greco, John Heatwole, Jane Larkindale, David R. Lynch, Courtney Park, Spencer Rosero, Sub Subramony, Anika Varma, Ellen Wagner, Susan Walther, Jennifer Weinstein, McKenzie Wells, Christine Zizzi, and Chad Heatwole: Patient Reported Impact of Symptoms in Friedreich's Ataxia (PRISM-FA). Neurology 2022 Notes: in press.

Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group.: Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 17(1): 415, Nov 2022.

Georgiou-Karistianis N, Corben LA, Reetz K, Adanyeguh IM, Corti M, Deelchand DK, Delatycki MB, Dogan I, Evans R, Farmer J, França MC, Gaetz W, Harding IH, Harris KS, Hersch S, Joules R, Joers JJ, Krishnan ML, Lax M, Lock EF, Lynch D, Mareci T, Muthuhetti Gamage S, Pandolfo M, Papoutsi M, Rezende TJR, Roberts TPL, Rosenberg JT, Romanzetti S, Schulz JB, Schilling T, Schwarz AJ, Subramony S, Yao B, Zicha S, Lenglet C, Henry PG.: A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol. PLOS 17(11): e0269649. Nov 2022.

Shen, M.M., Rodden, L. N., McIntyre, K., Arias, A., Profeta, V., Schadt, K., Lynch, D. R.: SARS-CoV-2 in patients with Friedreich Ataxia. Journal of Neurology 11(1-4.), Oct 2022.

Schur, G. M., Dunn, J., Nguyen, S., Dedio, A., Wade, K., Tamaroff, J., Clay, A., Mitta, N., Wilson, N., Serai, S., Wang, D.-J., Falk, M., Reddy, R., Lynch, D., McCormack, S. E.: In Vivo Assessment of OXPHOS Capacity using 3T CrCEST MRI in Friedreich’s Ataxia J Neurology 269(5): 2527-2538, May 2022.

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Last updated: 12/04/2022
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