SCoBIRC FACULTY

Kathryn E. Saatman, Ph.D.

Associate Professor
Spinal Cord & Brain Injury Research Center and Departments of Physiology & Neurosurgery

Ph.D. in Bioengineering from University of Pennsylvania (1993). Postdoctoral training at the Head Injury Center, University of Pennsylvania.

Research Interests

The Neuronal Cytoskeleton
The cytoskeleton is a dynamic structure, vital to the physical and functional integrity of neurons. The major components of the cytoskeleton in neurons of the central nervous system are neurofilaments, microtubules and actin filaments. The assembly and regulation of these elements are coordinated by a large number of associated proteins. A major focus in the Saatman lab is the investigation of the effects of traumatic brain injury (TBI) on the organization and integrity of the neuronal cytoskeleton. Using immunohistochemistry, immunoblotting and tract tracing techniques, changes in the cellular/subcellular distribution or levels of key cytoskeletal proteins such as neurofilament proteins, microtubule-associated protein-2 (MAP-2), actin, and spectrin are evaluated in models of contusive brain injury and traumatic axonal injury. The time course and mechanisms of trauma-induced disruptions in axonal transport, a process dependent on the microtubule cytoskeleton, are also studied. We have shown that certain cytoskeletal changes precede axonal degeneration and neuronal cell death caused by trauma. The Saatman lab utilizes novel transgenic and knockout mice to isolate the roles of specific cytoskeletal proteins in damage and recovery after traumatic injury.

Calpains in Neuronal Trauma
Prolonged increases in intracellular free calcium lead to neuronal damage through a number of mechanisms, including the activation of calpains. The activation of these neutral proteases is a feature of many neurodegenerative diseases and neuronal injury conditions, and is believed to be an early step in the cascade of events leading to neuronal death. We have established that calpains are activated very early after experimental TBI or traumatic axonal injury, and that prolonged activation correlates with cytoskeletal degradation and cell death in multiple brain regions. These studies have been complemented by experiments showing that posttraumatic inhibition of calpains improves functional outcome after trauma. Ongoing work is focused on developing improved methods for the inhibition of calpains in animal models of trauma, and increasing our understanding of downstream targets of calpains in injured neurons.

Therapeutic Intervention in TBI
Traumatic brain injury afflicts millions of people in the United States, often leaving survivors with permanent brain damage and persistent motor and cognitive dysfunction. Due to the limited potential of the brain for self-repair after trauma, many therapeutic intervention strategies are aimed at preventing the continuing cell death and axonal injury that are initiated after a TBI. The Saatman lab is active in preclinical testing of promising therapeutics that may reduce cell damage, cell death and behavioral dysfunction by targeting pathologies such as excitotoxicity, calcium overload, or growth factor deprivation. These experiments involve behavioral assessments using well characterized tests of motor and cognitive function in rodents and quantification of regional cell death and tissue damage. In this area of translational research, the lab continues to work on establishing rational targets for therapy, determining optimal therapeutic windows for treatment, and exploring combination therapy approaches.

Representative Publications

Saatman, K.E., D. Bozyczko-Coyne, V. Marcy, R. Siman, and T.K. McIntosh, "Prolonged Calpain-Mediated Spectrin Breakdown Occurs Regionally Following Experimental Brain Injury in the Rat." J. Neuropath. Exp. Neurol., v. 55(7), pp. 850-860; 1996.

Saatman, K.E., H. Murai, R.T. Bartus, D.H. Smith, N.J. Hayward, B.R. Perri, and T.K. McIntosh, "The Calpain Inhibitor AK295 Attenuates Motor and Cognitive Deficits Following Experimental Brain Injury in the Rat." Proc. Natl. Acad. Sci., v. 93(8), pp. 3428-3433; 1996.

Saatman, K.E., P.C. Contreras, D.H. Smith, R. Raghupathi, K.L. McDermott, S.C. Fernandez, K.L. Sanderson, M. Voddi, and T.K. McIntosh, "Insulin-Like Growth Factor-1 (IGF-1) Improves Both Neurological Motor and Cognitive Outcome Following Experimental Brain Injury." Exp. Neurol., v. 147, pp. 418-427; 1997.

Saatman, K.E., D.I. Graham, and T.K. McIntosh, "The Neuronal Cytoskeleton is at Risk After Mild and Moderate Brain Injury." J. Neurotrauma, v. 15(12), pp. 1047-1058; 1998.

Nakamura M., K.E. Saatman, J.E. Galvin, U. Scherbel, R. Raghupathi, J.Q. Trojanowski, and T.K. McIntosh, "Increased Vulnerability of NFH-LacZ Transgenic Mouse to Traumatic Brain Injury-Induced Behavioral Deficits and Cortical Damage." J. Cereb. Blood Flow Metab., v. 19, pp. 762-770; 1999.

Saatman, K.E., C. Zhang, R.T. Bartus, and T.K. McIntosh, "Behavioral Efficacy of Posttraumatic Calpain Inhibition is not Accompanied by Reduced Spectrin Proteolysis, Cortical Lesion, or Apoptosis." J. Cereb. Blood Flow Metab., v. 20(1), pp. 66-73; 2000.

Saatman, K.E., F.M. Bareyre, M.S. Grady and T.K. McIntosh, "Acute Cytoskeletal Alterations and Cell Death Induced by Experimental Brain Injury are Attenuated by Magnesium Treatment and Exacerbated by Magnesium Deficiency." J.Neuropath. Exp. Neurol., v. 60, pp. 183-194; 2001.

Huh, J.W., H.L. Laurer, R. Raghupathi, M.A. Helfaer, and K.E. Saatman, "Rapid Loss and Partial Recovery of Neurofilament Immunostaining Following Focal Brain Injury in Mice." Exp. Neurol., v. 175, pp. 198-208; 2002.

Saatman, K.E., B. Abai, A. Grosvenor, C. Vorwerk, D.H. Smith, and D.F. Meaney, "Traumatic Axonal Injury Results in Biphasic Calpain Activation and Retrograde Transport Impairment in Mice." J. Cereb. Blood Flow Metab., v. 23, pp. 34-42; 2003.

Saatman, K.E., K.J. Feeko, R.L. Pape, and R. Raghupathi, “Differential Behavioral and Histopathological Responses to Graded Cortical Impact Injury in Mice.” J. Neurotrauma, v. 23, pp. 1241-1253; 2006.

Lebesgue, D., D.G. LeBold, N.O. Surles, D.M. Morales, A.M. Etgen, R. Suzanne Zukin, and K.E. Saatman, “Effects of Estradiol on Cognition and Hippocampal Pathology after Lateral Fluid Percussion Brain Injury in Female Rats.” J. Neurotrauma, v. 23, pp. 1814-1827; 2006.

Serbest, G., M.F. Burkhardt, R. Siman, R. Raghupathi, and K.E. Saatman, “Temporal Profiles of Cytoskeletal Protein Loss Following Traumatic Axonal Injury in Mice.” Neurochem. Res., in press.