Faculty

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

Layne N Rodden, Christian Rummey, Yi Na Dong, Sarah Lagedrost, Sean Regner, Alicia Brocht, Khalaf Bushara, Martin B Delatycki, Christopher M Gomez, Katherine Mathews, Sarah Murray, Susan L Perlman, Bernard Ravina, S H Subramony, George Wilmot, Theresa Zesiewicz, Alessandra Bolotta, Alain Domissy, Christine Jespersen, Baohu Ji, Elisabetta Soragni, Joel M. Gottesfeld and David R Lynch: A non-synonymous SNP in SIRT6 predicts neurological severity in Friedreich ataxia. Frontiers in Molecular Biosciences 2022

Wang D, Ho ES, Cotticelli MG, Xu P, Napierala JS, Hauser LA, Napierala M, Himes BE, Wilson RB, Lynch DR, Mesaros C. : Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia. J Lipid Res 2022 Notes: in press.

Christian Rummey 1, Louise A Corben 2 3, Martin Delatycki 2 3, George Wilmot 4, Sub H Subramony 5, Manuela Corti 5, Khalaf Bushara 6, Antoine Duquette 7, Christopher Gomez 8, J Chad Hoyle 9, Richard Roxburgh 10, Lauren Seeberger 11, Grace Yoon 12, Katherine Mathews 13, Theresa Zesiewicz 14, Susan Perlman 15, David R Lynch 16: Natural History of Friedreich's Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design. Neurology 2022 Notes: in press.

Rodden, L. N., Rummey, C., Dong, Y.-N., Lynch, D.R.: Clinical evidence for variegated silencing in Friedreich ataxia patients. Neurology Genetics 8(3): e683, May 2022.

Vásquez-Trincado, C., Dunn, J., Han, J. I., Hymms, B., Tamaroff, J., Patel, M., Nguyen, S., Dedio, A., Wade, K., Enigwe, C., Nichtova, Z., Lynch, D. R., Csordas, G., McCormack, S. E., Seifert, E. L.: Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle. JCI Insight 7(9): e155201. May 2022.

Tamaroff, J., DeDio, A., Wade, K., Wells, M., Park, C., Leavens, K., Rummey, C., Kelly, A., Lynch, D. R., McCormack, S. E.: Friedreich’s Ataxia Related Diabetes: Epidemiology and Management Practices   Diabetes Research and Clinical Practice 186: 109828, Apr 2022.

Wang, Q., Laboureur, L., Weng, L., Eskenazi, N., Hauser, L. A., Mesaros, C., Lynch, D. R., Blair, I. A.: Simultaneous quantification of mitochondrial mature frataxin and extra-mitochondrial frataxin isoform E in Friedreich's ataxia blood. Frontiers Neurosci 16: 874768 Apr 2022.

Mercado-Ayon, E., Warren, N., Halawani, S. Ngaba, L., Dong, Y. N., Chang, J. C., Fonck, C., Mavilio, F., Lynch, D. R., Lin, H.: Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia. Frontier Neurosci 6: 819569, Mar 2022.

Rodden, L., Pook, M., Gottesfeld, J., Lam, C. ,Lynch, D. R., Blair, I., Messaros, C., Pandolfo, M., Rosjjakul, T., Dionisis, C., Gilliam, K., Bidichandani, S.: DNA methylation in Friedreich ataxia silences expression of frataxin isoform E. Sci Reports 12(1): 5031, Mar 2022.

Dunn, J., Tamaroff, J., DeDio, A., Nguyen, S., Wade, K., Cilenti1, N., Weber, D. R., Lynch, D. R., McCormack, S. E.: Bone mineral density and current bone health screening practices in Friedreich’s Ataxia. Frontiers in Neuroscience 16: 818750, Mar 2022.

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Last updated: 07/27/2022
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