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

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.

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.

Nellie Georgiou-Karistianis, Corben, Louise , Kathrin Reetz, Isaac Adanyeguh, Manuela Corti, Dinesh Deelchand, Martin Delatycki, Imis Dogan, Rebecca Evans,Jennifer Farmer, Marcondes França, William Gaetz, Ian Harding,Karen Harris, Steven Hersch,, Richard Joules, James Joers, Michelle Krishnan, Michelle Lax, Eric Lock, David Lynch, Thomas Mareci, "Sahan Muthuhetti Gamage, Massimo Pandolfo, Marina Papoutsi, Thiago Rezende, Timothy Roberts, Jens Rosenberg, Sandro Romanzetti, Jörg Schulz, Traci Schilling, Adam Schwarz, Sub Subramony, Bert Yao, "Stephen Zicha,Christophe Lenglet, Pierre-Gilles Henry: A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol. PLOS 2022 Notes: in press.

Dong, Y. N., Hsu, F. C., Koziol-White, C. J., Stepanova, V., Jude J., Gritsiuta, A., Rue, R., Mott, R., Coulter, D. A., Panettieri, R. A. Jr, Krymskaya, V. P., Takano, H., Goncharova, E. A., Goncharov, D. A., Cines, D. B., Lynch, D. R.: Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells. Sci Rep 11(1): 8205, Apr 2021

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Last updated: 06/15/2022
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