Leeheading.jpg
ksl3h@virginia.edu

Chair and Harrison Foundation
Professor of Neuroscience

Ph.D., 1979, University of California, Irvine

Stroke and Epilepsy: Mechanisms and Therapeutic Strategies

Our laboratory is interested in the cellular and molecular mechanisms of neuronal injury associated with stroke and epilepsy. A multidisciplinary approach has been undertaken to elucidate how neurons are destabilized in these neurological disorders. Knowledge from our basic investigations is then utilized to develop and test specific therapeutic strategies for rescuing damaged neurons. Several lines of investigation are currently underway in the laboratory, including:

  1. Elucidate mechanisms of neuronal tolerance to injury, and develop preconditioning stimuli that can be implemented clinically. Ischemic tolerance is a state in which neurons are made more resistant to injury after a preconditioning stimulus is given hours to days prior to injury. The induction of tolerance has the potential to limit brain injury during periods of anticipated ischemia, such as occur in cardiovascular and neurovascular surgeries.

  2. Define the roles of inflammatory events in cerebrovascular damage after hemorrhagic stroke. Identify the cells and signaling molecules contributing to cerebral vasospasm after a subarachnoid  hemorrhage.  Test specific anti-inflammatory agents for their ability to limit vasospasm.

  3. Evaluate the utility of adult multipotent cells for the treatment of stroke and traumatic brain injury. Test multipotent human cells extracted from lipoaspirate as a source for cell replacement therapy in animal models of cerebral injury.

  4. Test neuroprotective strategies for limiting the progression of ischemic stroke.

  5. Characterize how errors in neocortical development contribute to epilepsy. Neocortical development is being investigated in a novel mutant rat which exhibits subcortical band heterotopia (large collections of misplaced cells in the cortex) and epilepsy. The developmental and adult physiological mechanisms responsible for aberrant neural activity are being studied.

Representative Publications

  • Lee, K., Frank, S., Vanderklish, P., Aria, A., and Lynch, K. (1991) Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc. Nat'l. Acad. Sci. (USA ) 88: 7233-7237.
  • Hong, S., Goto, Y., Lanzino, G., Soleau, S., Kassell, N., and Lee, K. (1994) Neuroprotection with the calpain inhibitor in a model of focal cerebral ischemia. Stroke 25: 663-669.
  • Lee, K. (1996) The role of calcium-activated proteolysis in neuronal injury. In: Novel Therapies for CNS injuries: Rationales and Results. P. Peterson and J.W. Phillis (eds.) CRC Press, Inc., pp. 347-361.
  • Wang, K., Nath, R., Posner, A. Raser, K., Buroker-Kilgore, M., Hajimohammadreza, I., Probert, A., Marcoux, F., Ye, Q., Takano, E., Hatanaka, M., Maki, M., Caner, H., Collins, J., Fergus, A., Lee, K., Lunney, E., Hays, S. and Yuen, P., An alpha-mercaptoacrylic acid derivative is a selective non-peptide cell-permeable calpain inhibitor and is neuroprotective. Proc. Nat’l Acad Sci (USA ) 93: 6687-6692 (1996).
  • Fergus, A. and Lee, K., GABAergic regulation of cerebral microvascular tone in the rat. J   Cerebral Blood Flow and Metabol 17: 992-1003 (1997).
  • Lee, K., Schottler, F., Collins, J., Lanzino, G., Couture, D., Rao, A., Hiramatsu, K., Goto, Y., Hong, S-C., Caner, H., Yamamoto, H., Berr, S., Omary, R., Jackson, T., Goble, J., Scrable, H., Bertram, E. and Chen, Z-F., A genetic animal model of human neocortical heterotopia associated with seizures, J. Neuroscience 17: 6236-6242 (1997).
  • Schottler, F., Couture, D., Rao, A, Kahn, H. and Lee, K., Subcortical connections of normotopic and heterotopic neurons in the somatosensory cortex of the tish mutant rat J Comp Neurol 395: 29-42 (1998).
  • Bavbek, M., Kwan, A-L, Polin, R., Kassell, N. and Lee, K., Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Stroke 29: 1930-1935 (1998).
  • Polin, R., Bavbak, M., Shaffrey, M., Chadduck, J., Bogaev, C., Kaptain, G., Billups, K., Kassell, N. and Lee, K., Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage, J. Neurosurgery 89: 559-567 (1998).
  • Lee, K., Collins, J., Anzivino, M., Frankel, E., and Schottler, F., Heterotopic neurogenesis in a rat with cortical heterotopia J. Neuroscience 18: 9365-9375 (1998).
  • Wang, K.K.W., Yuen, P-W. and Lee, K., Calpain in excitotoxicity, cerebral ischemia and neuronal apoptosis. in Calpain: Pharmacology and Toxicology of a Calcium-dependent Cellular Protease, ed. K.K.W. Wang and P.-W. Wai. Taylor and Francis, Bristol , PA (1999) pp. 179-190.
  • Chen, Z-F., Schottler, F. Bertram, E., Gall, C.M, Anzivino, M.J. and Lee, K., Distribution and initiation of seizure activity in a rat brain with subcortical band heterotopia. Epilepsia 41: 493-501 (2000).
  • Nishio, S., Yunoki, M., Chen, Z-F., Anzivino, M.J. and Lee, K., Ischemic tolerance in the rat neocortex following hypothermic preconditioning. J. Neurosurgery 93: 845-851 (2000).
  • Chen, Z-F, Kamiryo, T., Henson, S.L., Yamamoto, H., Bertram, E.H., Schottler, F., Patel, F., Steiner, L., Prasad D., Kassell, N.F., Shareghis, S. and Lee, K., Anticonvulsant effects of gamma surgery in a rat model of chronic spontaneous limbic epilepsy. J. Neurosurgery 94: 270-280 (2001).
  • Schottler, F., Fabiato, H., Leland, J.M., Chang, L-Y., Lotfi, P. and Lee, K., Normotopic and heterotopic cortical representations of mystacial vibrissae in a rat with subcortical band heterotopia Neuroscience 108: 217-235 (2001).
  • Yunoki, M., Nishio, S., Anzivino, M.A. and Lee, K., Characteristics of hypothermic preconditioning influencing the induction of delayed ischemic tolerance J. Neurosurgery 97: 650-657 (2002).
  • Dumont, A.S., Dumont, R.J., Chow, M.M., Lin, C-L., Callaynseller, T. Ley, K.F., Kassell, N.F., and Lee, K., Cerebral vasospasm following subarachnoid hemorrhage: putative role of inflammation, Neurosurgery 53, 123-135 (2003).
  • Yunoki, M., Nishio, S., Anzivino, M.J., and Lee, K., Hypothermic preconditioning induces rapid tolerance to focal ischemic injury in the rat. Exp Neurol 181L 291-399 (2003).
  • Lee, K. , Anzivino, M.J., Machizawa, M.G., Zhang, F., Williams, C., Schottler, F., Tsuchitani, S.,   Drummond, J., Kinard, C.L., Bertram, E., Trotter, S., Kapur, J., and Chen, Z.-F., Structural and functional deficits in a rat model of cortical heterotopia, in: The Extraordinary Brain Series: Developing New Pathways in the Study of the Dyslexic Brain. (2004).