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.
Long, A., Napierala, J.S., Polak, U.,Hauser, L., Koeppen, A. H., Lynch, D. R., Napierala: Somatic instability of the expanded GAA repeats in Friedreich’s ataxia PLOS : 2018.
McCormick, A., Shinnick, J., Schadt, K., Rodriguez, R., Addonizio, L., Hirano, M., Perlman, S., Lin, K.Y., Lynch: Cardiac transplantation in Friedreich Ataxia: Extended follow-up.
J Neurol Sci. 375 : 471-473,2017.
Napierala, J. S., Li,Y., Lu,Y., Lin,K., Hauser, L.A., Lynch, D. R., Napierala: Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers Disease models and mechanisms 10 (11): 1353-1369.,2017.
Lin, H., Magrane, J., Rattelle, A., Stepanova,A., Galkin, A., Clark, E. M., Dong, Y.-N., Halawani, S. M., Lynch: Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia Disease Models and Mechanisms 10 (11): 1343-1352.,2017.
McCormick, A., Farmer, J., Perlman, S., Delatycki, M., Wilmot, G., Matthews, K., Yoon, G., Hoyle, C., Subramony, S.H., Zesiewicz, T., Lynch, D.R., McCormack: Impact of Diabetes in the Friedreich Ataxia Clinical Outcome Measure Study Annals of Clinical and Translational Neurology 4 (9): 622-631,2017.
Clark, E. M., Butler, J.S., Isaacs, C. J., Napierela, M., Lynch: Selected missense mutations impair frataxin processing in Friedreich ataxia
Annals of Clinical and Translational Neurology 4 (8): 575-584.,2017.
DeBrosse, C., Nanga, R. P. R., Wilson, N., D’Aquilla, K., Elliott, M.,Hariharan, H., Yan, F., Wade, K., Nguyen, S.,Worsley, D., Parris-Skeete, C., McCormick, ,E.,Xiao, R., Cunningham, Z. Z., Fishbein, L., Nathanson, K.L., Lynch, D. R., Stallings, V. A., Yudkoff, M., Falk, M. J. Reddy, R. R., McCormack: Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders Journal of Clinical Investigation Insight 1 (18): e88207.,2016.
Isaacs, C.J., Brigatti, K.W., Kucheruk, O., Ratcliffe, S., Sciascia, T., McCormack, S. E., Willi, S.W., Lynch: Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia
Muscle and Nerve 54 (5): 887-894,2016.
Shinnick, J.E., Schadt, K., Strawser, C., Wilcox, N., Perlman, S.L., Wilmot, G.R., Gomez, C.M., Mathews, K.D., Yoon, G., Zesiewicz, T., Hoyle,, C., Subramony, S.H., Yiu, E., Delatycki, M.B., Brocht, A.F. Farmer, J.M., Lynch: Co-Morbid Medical Conditions in Friedreich Ataxia: Association with Inflammatory Bowel Disease and Growth Hormone Deficiency
Journal of Child Neurology 31 (9): 1161-5.,2016.
Li, Y.,Polak, U., Clark, A.D., Bhalla, A.,Chen, Y.-Y., Li, J, Farmer, J., Seyer, L., Lynch, D., Butler, J.S.: Establishing and maintenance of primary fibroblast repositories for rare diseases – Friedreich’s ataxia example Biopreservation and Biobanking 14 (4): 324-329.,2016.