Description of Research Expertise:
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.
Puligedda, R., Devi, C., Fetwehal, S, Uvaru, L, Kouiavskaia, D, Chumakov, K, Lynch, D, Prend, G, Kaushik, R., Dessain, : Capture and display of antibodies secreted by hybridoma cells enables fluorescent on-cell screening Monoclonal Antibodes 22 : 1-13,2019.
Lynch DR, Hauser L, McCormick A, Wells M, Dong YN, McCormack S, Schadt K, Perlman S, Subramony SH, Mathews KD, Brocht A, Ball J, Perdok R, Grahn A, Vescio T, Sherman JW, Farmer JM: Randomized, Double-Blind, Placebo-Controlled Study of Interferon- γ1b in Friedreich Ataxia Annals of Clinical and Translational Neurology 6 (3): 546-553,2019.
Jacobi, A. A, Halawani, S., Lynch, D.R., Lin, H: Neuronal serine racemase associates with Disrupted-In-Schizophrenia-1 and DISC1 agglomerates: Implications for schizophrenia Neurosci Lett 692: : 107-114,2019.
Xavier, Pandolgo, Gaetz, Lnch: Evidence for genetically determined degeneration of proprioceptive tracts in Friedreich ataxia Neurology : 2019.
Dong, Y, Mcmillan E, Clark E, Lin H, Lynch DR: GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models Human Mol Genet : 2019.
Clark, E., Schadt, K., Strawser, C., Lynch, D. R.: Identification of a Novel Missense Mutation in Friedreich’s Ataxia –FXNW168R Annals Clin Translational Neurol : 2019.
Guo, L., Wang, Q., Weng, L., Hauser, L., Strawser, C., Mesaros, Lynch, D.R., Blair, I: Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes Sci Reports 8 (1): 17043,2018.
Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C: Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia Ann Clin Transl Neurol 6 (1): 15-26,2018.
Nachun, D., Gao, F., Isaacs, C., Strawser, C., Yang, Z., Dokuru, D., Van Berlo, V., Sears, R, Farmer, J., Perlman, S., Lynch, D.R., Coppola, G.: Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich’s ataxia patients Hum Molec Genet 27 (17): 2965-2977,2018.
Zesiewicz, T., Salemi, J.L., Perlman, S., Sullivan, K. L., Shaw, J. D. Huang, Y., Isaacs, C., Gooch, C., Lynch, D. R., Klein, M. B.: Double-blind, Randomized, Controlled Trial of EPI-743 in Friedreich’s Ataxia Neurodegen Dis Management 8 (4): 233-242.,2018.