Research Interests:

Pharmacological control of N-methyl-daspartate receptors.

Keywords:

Gluatamte, NMDA , excitotoxicity.

Research Summary:

Dr. Lynch's basic research has been directed toward understanding the pharmacological features of the N ­ methyl-D- Aspartate receptor using molecular biological approaches.  This glutamate receptor is a crucial component of excitotoxicity, a pathophysiological mechanism of acute and chronic neurologic disorders.  Dr. Lynch's work has concentrating on defining the properties of specific subtypes of NMDA receptors, in order to define therapeutic agents and approaches that ameliorate excitotoxicity without producing significant side effects.  The initial studies from his lab used site directed mutagenesis to define the structural components of NMDA receptors that mediate subtype specific stimulation by polyamines and subtype specific inhibition by agents such as ifenprodil and haloperidol.  Subsequent experiments have defined structural components of the receptor mediating subtype specific modulation of the NMDA receptor by protein kinase C.  In these investigations, Dr. Lynch's lab also linked specific NMDA receptor subtypes to increased levels of cell death and reactive oxygen species production, connecting their cellular work with mechanisms of neuronal degeneration.  The most recent work links subtype specific NMDA receptor activation of calpain, and demonstrates that this enzyme may control turnover of NMDA receptors under excitotoxic conditions.  Calpain, an enzyme activated selectively by NMDA receptors, also may play a crucial role in protein turnover of other disease causing proteins such as alpha synuclein, further associating Dr. Lynch's laboratory investigations with pathophysiological mechanisms of neurological disorders.  Dr. Lynch has been continuously supported by the NIH for his NMDA receptor work since 5/95.

Potential Lab Rotation Projects:

1. Examination of mechansims of NMDA receptor turnover, and mapping of biochemcial modulation sites by calpain.

2. Definition of signalling pathways activated by NMDA receptor subtypes.

Key References:

Guttmann, R. P., Baker, D. L., Seifert, K. S., Cohen, A., Coulter, D. A., and Lynch, D. R. Specific proteolysis of the NR2 subunit at multiple sites by calpain. J. Neurochem. 78:1083-1093, 2001.

Grant, E. R., Guttmann, R. P., Seifert, K. M., and Lynch, D. R. A region of the N-methyl- D-aspartate receptor 2A subunit that is sufficient for potentiation by phorbol esters.  Neurosci. Lett. 310:9-12, 2001.

Guttmann, R. P., Sokol, S., Simpkins, K., Baker, D. L., Dong, Y., and Lynch, D. R. Proteolysis of the NMDA receptor by calpain in situ. J. Phamacol. Exp. Ther. 302:1023-1030, 2002.

Mishizen-Eberz, A. J., Guttmann, R. P., Giasson, B. I., Day, G. A. III, Hodara, R., Ischiropoulos, H., Lee, V. M.-Y., Trojanowski, J. Q., and Lynch, D. R. Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J. Neurochem. 86:836-47, 2003.

Simpkins, K., Guttmann, R. P. Dong, Y. Chen, Z., Sokol, S., Neumar, R. W. and Lynch, D. R. Selective activation induced cleavage of the NR2B subunit by calpain. J. Neurosci 23:11322-31, 2003.