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.
Yang, Y.,Zhang, L.,Lynch, D. R., Lukas, T. Ahmeti, K., Sleiman, P.M.A., Ryan, E., Schadt, K. A., Newman, J. H., Siddique, N., Siddique, T.: Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis Neurology Genetics 2 (2): e60,2016.
Galea, C. A., Huq, A., Lockhart, P.J., Tai, G. Corben, L.A., Yiu, E. M., Gurrin, L. C., Lynch, D. R., Gelbard, S., Durr, A., Pousset11, F., Parkinson, M., Labrum, R., Giunti, P., Perlman, S. L., Delatycki, M. B., and Evans-Galea, M. V.: Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia Annals of Neurology 79 (3): 485-95.,2016.
Lin, H.,Jacobi, A.A., Anderson, S.A, Lynch, D.R.: Postsynaptic D-serine modulates serine racemase/PSD95 signaling and glutamatergic synapse formation in an autocrine manner Frontiers in Cellular Neuroscience 10 (34): doi: 10.3389/fncel.2016.00034.,2016.
Shinnick, J. , Isaacs, C. J., Vivaldi, S., Schadt, K. A., Lynch, D. R.: Friedreich Ataxia and Nephrotic Syndrome: A Series of Two Patients BMC Neurology 16 (1): 3,2016.
Bhalla,A. D., Jamayran, A.K., Li, Y., Lynch, D. R., Napierala, M.: Deep sequencing of mitochondrial genomes reveals increased mutation load in Friedreich’s Ataxia Annals of Clinical and Translational Neurology : 2016.
Li, Y.,Polak, U., Clark, A.D., Bhalla, A.,Chen, Y.-Y., Li, J, Farmer, J., Seyer, L., Lynch, D., Butler, J.S., M. Napierala: Establishing and maintenance of primary fibroblast repositories for rare diseases – Friedreich’s ataxia example Biopreservation and Biobanking : 2016.
Isaacs, C.J., Brigatti, K.W., Kucheruk, O., Ratcliffe, S., Sciascia, T., McCormack, S. E., Willi, S.W., Lynch, D.R.: Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia Muscle and Nerve : 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, D.R.: Co-Morbid Medical Conditions in Friedreich Ataxia: Association with Inflammatory Bowel Disease and Growth Hormone Deficiency Journal of Child Neurology : 2016.
Li, Y. Lu, Y., Polak, U., Lin, K., Shen,J.,Farmer, J. Seyer, L., Bhalla1, A.D, Rozwadowska, N., Lynch, D.R.,Butler, J. S., Napierala, M: Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus Human Molecular Genetics 24 (24): 6932-43,2015.
Lazaropoulos, M. Dong, Y., Clark,E.,Greeley, N. R.,Seyer, L.A., Brigatti,K. W., Christie, C., Perlman, S. L., Wilmot, G.R.,. Gomez, C. M. Mathews, K. D.,Yoon, G., Zesiewicz, T., Hoyle, C.,. Subramony, S.H., Brocht, A. F., Farmer, J. M., Wilson, R. B., Deutsch, E. C., Lynch, D. R.: Frataxin levels in peripheral tissue in Friedreich Ataxia Annals of Clinical and Translational Neurology 2 (8): 831-42.,2015.