SCoBIRC FACULTY

James W. Geddes, Ph.D.

Associate Director, SCoBIRC
Professor, Department of Anatomy and Neurobiology

Research Interests

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. Tetracycline-mediated regulation of gene expression is currently under investigation as a strategy to regulate the timing, magnitude, and duration of lentiviral-mediated calpastatin expression in vitro and in vivo.

Representative Publications

Zhang, S.-X., Underwood, M., Gibson, S., Huang, F.-f., Springer, J.E. and Geddes, J.W. Cytoskeletal disruption following contusion injury to the rat spinal cord. J. Neuropathol. Exp. Neurol. 59: 287-296, 2000.

Zhang, S.-x., Bondada, V., and Geddes, J.W. Evaluation of conditions for calpain inhibition in the rat spinal cord: effective postinjury inhibition with intraspinal MDL28170 microinjection. J. Neurotrauma 20: 59-67, 2003.

Pang, Z., Bondada, V., Zhang, S.-x., Sengoku, T., Siman, R. and Geddes, J.W. Calpain facilitates the neuron death induced by 3-nitropropionic acid and contributes to the necrotic morphology. J. Neuropathol. Exp. Neurol. 62: 633-643, 2003.

Sengoku, T., Bondada, V., Hassane, D., Dubal, S., and Geddes, J.W. Tat-calpastatin fusion proteins transduce rat primary neurons but do not inhibit cellular calpain activity. Exp. Neurol. 88:161-170, 2004.

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