James W. Geddes, Ph.D.
Associate Director, SCoBIRC
Using cell cultures and animal models, Dr. Geddes' lab is investigating mechanisms implicated in the secondary neurodegeneration following spinal cord injury. The primary focus is on the role of calpain, a Ca2+-activated protease, and the potential of calpain inhibition as a therapeutic intervention following spinal cord injury.
There is substantial evidence that calpain inhibition represents a rational target for postinjury therapeutic intervention following traumatic CNS injury. Calpain activation is strongly implicated in the necrotic cell death that predominates postinjury. Calpain activity is elevated for several hours postinjury, providing a reasonable therapeutic window for intervention.
Dr. Geddes' lab is examining various strategies for calpain inhibition. Current synthetic calpain inhibitors suffer from weak potency, poor specificity, and short plasma half-lives. New inhibitors offer greater solubility and their efficacy may be further improved by direct intraspinal injection of intrathecal administration. Additional strategies include viral vectors to elevate cellular levels of calpastatin, an endogenous calpain inhibitor, or to knock down levels of individual calpain isoforms via siRNA. Based on their finding that mu-calpain is present in the mitochondrial intermembrane space, Dr. Geddes and colleagues are also examining the substrates and role of mitochondrial mu-calpain.
Reneer DV, Hisel RD, Hoffman JM, Kryscio RJ, Lusk BT, Geddes JW. A multi-mode shock tube for investigation of blast-induced traumatic brain injury. J. Neurotrauma 28: 95-104, 2011.
Cullen DK, Xu Y, Reneer DV, Browne KD, Geddes JW, Yang S, Smith DH.Color changing photonic crystals detect blast exposure. Neuroimage 54 Suppl1:S37-44, 2011.
Geddes JW, Saatman KE.Targeting individual calpain isoforms for neuroprotection. (Commentary) Exp. Neurol 226: 6-7, 2010.
Naga KK, Geddes JW. Dimebon Inhibits Calcium-Induced Swelling of Rat Brain Mitochondria But Does Not Alter Calcium Retention or Cytochrome C Release. Neuromolecular Med. 2010 Jul 13. [Epub ahead of print]
Yu CG, Yezierski RP, Joshi A, Raza K, Li Y, Geddes JW. Involvement of ERK2 in traumatic spinal cord injury. J Neurochem 113: 131-142, 2010
Li Y, Bondada V, Joshi A, Geddes JW.Calpain 1 and Calpastatin expression is developmentally regulated in rat brain. Exp. Neurol. 220: 316-9, 2010.
Joshi, A., Bondada, V., and Geddes, J.W. Mitochondrial mu-calpain is not involved in the processing of aoptosis-inducing factor. Exp. Neurol. 218: 221-227, 2009.
Badugu, R., Garcia, M., Bondada, V., Joshi, A., and Geddes, J.W. N-terminus of calpain 1 is a mitochondrial targeting sequence. J. Biol. Chem 283: 3409-3417, 2008.
Naga, K.K., Sullivan, P.G. and Geddes, J. W. High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J. Neurosci. 27: 7469-7575, 2007.
Yu, C.G., Joshi, A. and Geddes, J.W. Intraspinal MDL28170 microinjection improves functional and pathological outcome following spinal cord injury. J. Neurotrauma 25: 833-840, 2008.
University of Kentucky
Tel: (859) 323-5135