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

Thomas-Black, G., Dumitrascu, A., Garcia-Moreno, H., Vallortigara, J., Greenfield, J., Hunt, B., Walther, S., Wells, M., Lynch, D. R., Montgomery, H., Giunti, P.: The Attitude of Patients with Progressive Ataxias Towards Clinical Trials. Orphanet Journal of Rare Diseases 17(1): 1, Jan 2022.

Dong YN, Hsu FC, Koziol-White CJ, Stepanova V, Jude J, Gritsiuta A, Rue R, Mott R, Coulter DA, Panettieri RA Jr, Krymskaya VP, Takano H, Goncharova EA, Goncharov DA, Cines DB, Lynch DR.: Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells. Sci Rep 11(1): 8205. Apr 2021

Maya Patel, Ashley McCormick, Jaclyn Tamaroff, Julia Dunn, Jonathan A. Mitchell, Kimberly Y. Lin, Jennifer Farmer, Christian Rummey, Susan L. Perlman, Martin B Delatycki, George R. Wilmot, Katherine D. Mathews, Grace Yoon, Joseph Hoyle, Manuela Corti, S. H. Subramony, Theresa Zesiewicz, David Lynch, and Shana McCormack: Body mass index and height in the Friedreich Ataxia Clinical Outcome Measures Study. Neurology Genetics 7(6): e638, Nov 2021.

Li, Yanjie; Li, Jixue; Wang, Jun; LYNCH, David; Shen, Xiulong; COREY, DAVID; Parekh, Darshan ; Bhat, Balkrishen; Woo, Caroline; Cherry, Jonathan; Napierala, Jill; Napierala, Marek: Targeting 3’ and 5’ Untranslated Regions with Antisense Oligonucleotides to Stabilize Frataxin mRNA and Increase Protein Expression. Nucleic acids Research 49(20): 11560-11574, Nov 2021.

Mueller, A., Paterson, E., McIntosh, A., Praestgaard, J., Bylo, M., Hoefling, H., Wells, M., Lynch, D., Rummey, C., Krishnan, M., Schultz, M., Malanga, C.J.: Digital endpoints for self-administered home-based functional assessment in Friedreich’s ataxia. Annals of Clin Trans Neurol 8(9): 1845-1856. Sep 2021.

Cherian, D., Schadt, K., Park, C., Veasey, S., Goldberg, D., Lynch, D.: Coexistence of Tyrosinemia and Friedreich Ataxia in a Single Patient: Treatment with Liver Transplantation. Annals of Case Reports 6: 581, jun 2021 Notes: DOI: 10.29011/2574-7754.100581.

Wang, H.,Norton, J., Linsu, D.R., Demartinis, N., Sen, R., Shah, A., Farmer, J.M., Lynch, D.R.: Results of a randomized double-blind study evaluating luvadaxistat in adults with Friedreich ataxia. Annals of Clinical Translational Neurology 8(6): 1343-1352. Jun 2021.

Rummey, C., Flynn, J. M. , Corben, L. A., Delatycki, M. B., Wilmot, G., Subramony, S. H., Bushara, K., Duquette, A., Gomez, C. M., Hoyle, J. C., Roxburgh, R., Seeberger, L., Yoon, G., Mathews, K. D., Zesiewicz, T., Perlman, S. , and Lynch, D. R. : Scoliosis in Friedreich’s Ataxia: Longitudinal Characterization in a Large Heterogeneous Cohort. Annals of Clinical and Translational Neurology 8(6): 1239-1250. Jun 2021.

Napierala, J.S., Rajapakshe, K., Clark, A., Chen, Y.Y., Huang, S., Mesaros, C., Xu, P., Blair, I.A., Hauser, L.A., Farmer, J., Lynch, D.R., Edwards, D.P., Coarfa, C., Napierala, M.: Reverse phase protein array reveals correlation of retinoic acid metabolism with cardiomyopathy in Friedreich’s ataxia Molecular Cellular Proteomics 20: 100094. May 2021.

Johnson, J., Mercado-Ayon, E., Clark, E., Lynch, D. R., Lin, H.: Drp1-dependent peptides reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia. Pharmacology Research & Perspectives 9(3): e00755. May 2021.

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Last updated: 01/06/2022
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