Faculty

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
Education:
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

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

Rodríguez-Pascau L, Britti E, Calap-Quintana P, Dong YN, Vergara C, Delaspre F, Medina M, Tamarit J, Pallardó FV, Gonzalez-Cabo P, Ros J, Lynch DR, Martinell M, Pizcueta P: PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia. Neurobiol Dis. 148: 105162. Jan 2021.

Joseph Johnson, Elizabeth Mercado-Ayon, Elisia Clark, David R Lynch*, Hong Lin*: Drp1-dependent peptides reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia. Pharmacology Research & Perspectives 2021 Notes: in press.

E.Mejia, A. Lynch, P. Hearle, O. Okunowo, H. Griffis, M. Shah, D. Lynch, K. Y. Lin : Ectopic Burden Via Holter Monitors in Friedreich’s Ataxia Pediatric Neurology 2021 Notes: in press.

Lynch, D. R., Johnson, J.: Omaveloxolone: Potential new therapy for Friedreich ataxia. Neurodegenerative disease management 2021 Notes: in press.

Rodden, L. N., Chutake,Y. K., Gilliam,K., Lam,C., Soragni,E., Hauser, L., Gilliam, M., Wiley, G., Anderson, M. P., Gottesfeld, J. M., Lynch, D. R., Bidichandani, S. I.: Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia. Hum Mol Genet 2021 Notes: in press.

Alexandra Clay, Kristin M Obrochta, Russell K Soon Jr, Christopher B Russell, and David R Lynch : Neurofilament Light Chain as a potential biomarker of disease status in Friedreich Ataxia Journal of Neurology 267(9): 2594-2598. Sep 2020.

L.Weng, L. Laboureur, Q. Wang, L. Guo, P. Xu, L. Gottlieb, David R. Lynch, Clementina Mesaros, I A. Blair: Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia. Scientific Reports 10(1): 15788, Sep 2020.

Christian Rummey, Theresa A. Zesiewicz, Santiago Perez Lloret, Jennifer M. Farmer, Massimo Pandolfo, David R. Lynch: Test-Retest Reliability of the Friedreich’s Ataxia Rating Scale. Annals of Clinical and Translational Neurology 7(9): 1708-12, Aug 2020.

Misiorek, J. O., Schreiber, A. M., Urbanek-Trzeciak, M. O., Jazurek-Ciesiołka, M., Hauser, L. A., Lynch, D. R., Napierala, J. S., Napierala, M.: A comprehensive transcriptome analysis identifies FXN and BDNF as novel targets of miRNAs in Friedreich’s ataxia patients. Mol Neurobio 57(8): 2639-2653. Jun 2020.

Afsharian, P., Nolan-Kenney,R., Lynch, A. E., Balcer, L. J., Lynch, D. R.: Correlation of visual quality of life with clinical and visual status in Friedreich ataxia. Journal of Neuroophthalmology 40(2): 213-217. . Jun 2020.

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Last updated: 02/27/2021
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