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

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 .

Seabury J, Varma A, Weinstein J, Rosero SJ, Engebrecht C, Khosa S, Zizzi C, Wagner ES, Alexandrou D, Cohen BL, Dilek N, Heatwole JM, Lynch DR, Park CC, Wells M, Subramony SH, Heatwole CR.: Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure. Neurol Clin Pract. 14 (3): e200303.,2024.

Cilenti, N. A., Tamaroff, J. G., Capiola, J. G., Faig, W., McBride, M. G., Paridon, S. M., O’Malley, S., Edelson, J. B., Lynch, D. R., McCormack, S. E., Lin, K. Y.: Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich Ataxia Muscle Nerve 69 (5): 613-619,2024.

Rummey, C., Subramony, S. H., Perlman, S. L., Farmer, J. M., Lynch, D. R.: Clinical research measures in children with Friedreich Ataxia:The FA-CHILD Study Annals of Clinical and Translational Neurology 11 (5): 1290-1300,2024.

Lynch, D. R., Sharma, S., Hearle, P., Greeley, N., Gunther, K., Keita, M., Strawser, C., Hauser, L., Park, C., Schadt, K., Lin, K.Y.: Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich Ataxia J. Neurol Sci 461 (123053): 2024.

Shen, M., Rummey, C., Lynch, D. R.: Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort Annals of Clinical and Translational Neurology 11 (5): 1110-1121,2024.

Lynch, D. R., Rojsajjakul, T., Subramony, S. H., Perlman, S. L., Keita, M., Mesaros, C., Blair, I. A.: Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort Journal of Neurology 271 (4): 1844-1849.,2024.

Dong, Y.-N., Ngaba, L. V., An, J., Adeshina, M. W., Warren, N., Wong, J., Lynch, D. R.: A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models Frontiers in Pharmacology-Neuropharmacology 15 (1): 1352311,2024.

Xu, Y., Song, R., Perszyk, R.E., Chen, W., Kim, S., Park, K., Allen, J.P., Nocilla, K.A., Zhang, J., XiangWei, W., Tankovic, A., McDaniels, E.D., Sheikh, R., Mizu, R.K., Karamchandani, M.M., Hu, C., Kusumoto, H., Pecha, J., Cappuccio, G., Gaitanis, J., Sullivan, J., Shashi, V., Petrovski, S., Jauss, R.-T., Lee, H.K., Bozarth, X., Lynch, D.R., Helbig, I., Pierson, T.M., Boerkoel, C.F., Myers, S.J., Lemke, J.R., Benke, T.A., Yuan, H., Traynelis, S.F.: De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor Cellular and Molecular Life Sciences 81 (1): 153,2024.

Chang, J.C., Ryan, M.R., Stark, M.C., Liu, S., Purushothaman, P., Bolan, F., Johnson, C.A., Champe, M., Meng, H., Lawlor, M.W., Halawani, S., Ngaba, L.V., Lynch, D.R., Davis, C., Gonzalo-Gil, E., Lutz, C., Urbinati, F., Medicherla, B., Fonck, C.: AAV8 Gene Therapy Reverses Cardiac Pathology and Prevents Early Mortality in a Mouse Model of Friedreich’s Ataxia Molecular Therapy Methods & Clinical Development 32 (1): 101193.,2024.

Academic Contact Information

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