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

Mercado Ayón, E., Talgo, E., Flatley, L., Coulman, J., Lynch, D. R.: Neurochemical Alterations in the Cerebellum in Friedreich’s Ataxia Mouse Models. Experimental Neurology 386 : 115176,2025.

Joseph, D.J., Mercado-Ayon, E., Flatley, L., Viaene, A. N., Hordeaux, J., Marsh, E. D., Lynch, D. R.: Functional Characterization of Parallel fiber-Purkinje Cell Synapses in two Friedreich’s Ataxia Mouse Models Cerebellum 24 (2): 42,2025.

Lynch, D.R., Subramony, S.H., Lin, K.Y., Mathews, K., Perlman, S., Yoon, G., Rummey, C.: Characterization of cardiac-onset initial presentation in Friedreich Ataxia Pediatric Cardiology. 46 (2): 379-382,2025.

Katherine Gunther1, Victoria Profeta1, Medina Keita1, Courtney Park1, McKenzie Wells1, Sonal Sharma1, 2, Kimberly Schadt1, and David R. Lynch: Safety Monitoring of Omaveloxolone in Friedreich Ataxia: Results from one year of clinical treatment Neurology and Therapy : 2025.

Georgiou-Karistianis N, Corben LA, Lock EF, Bujalka H, Adanyeguh I, Corti M, Deelchand DK, Delatycki MB, Dogan I, Farmer J, França MC Jr, Gabay AS, Gaetz W, Harding IH, Joers J, Lax MA, Li J, Lynch DR, Mareci TH, Martinez ARM, Pandolfo M, Papoutsi M, Parker RG, Reetz K, Rezende TJR, Roberts TP, Romanzetti S, Rudko DA, Saha S, Schulz JB, Subramony SH, Supramaniam VG, Lenglet C, Henry PG.: Neuroimaging biomarkers for Friedreich ataxia: a cross-sectional analysis of TRACK-FA Ann Neurol : 2025.

Perry CE, Halawani SM, Mukherjee S, Ngaba LV, Lieu M, Lee WD, Davis JG, Adzika GK, Bebenek AN, Bazianos DD, Chen B, Mercado-Ayon E, Flatley LP, Suryawanshi AP, Ho I, Rabinowitz JD, Serai SD, Biko DM, Tamaroff J, DeDio A, Wade K, Lin KY, Livingston DJ, McCormack SE, Lynch DR, Baur JA.: NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia. JCI Insight 9 (16): e177152,2024 .

Gerhart BJ, Pellerin D, Danzi MC, Zuchner S, Brais B, Matos-Rodrigues G, Nussenzweig A, Usdin K, Park CC, Napierala JS, Lynch DR, Napierala M.: Assessment of the clinical interactions of GAA repeat expansions in FGF14 and FXN Neurology Genetics 10 (6): e200210. ,2024.

Brandon J. Gerhart1, David Pellerin2, 3, Matt C. Danzi4, Stephan Zuchner4, Bernard Brais2, 5, Gabriel Matos-Rodrigues6, Andre Nussenzweig6, Karen Usdin7, Courtney C. Park8, Jill S. Napierala1, David R. Lynch8 and Marek Napierala1.: Assessment of the clinical interactions of GAA repeat expansions in FGF14 and FXN Neurol Genetics 10 (6): e200210.,2024.

Mishra, RK, Nunes, AS, Enriquez, A, Profeta, VR, Wells, M, Lynch, DR, Vaziri, A: At-home Wearable-based Monitoring and Machine Learning Predicts Clinical Measures and Biological Biomarkers of Disease Severity in Friedreich's Ataxia Communications Medicine. 4 (1): 217,2024.

O'Brien EM, Neiswinter N, Lin KY, Lynch D, Baldwin K, Profeta V, Flynn JM, Muhly WT.: Perioperative Management and Outcomes for Posterior Spinal Fusion in Patients with Friedreich Ataxia: A Single-Center, Retrospective Study Pediatric Anesthesia 34 (7): 654-661,2024.

Academic Contact Information

502 Abramson Center
Children's Hospital of Philadelphia
Philadelphia, PA 19104
Phone: 215-590-2242
Patient appointments: 800-789-7366