RESEARCH INTERESTS
Mechanisms of neuronal injury after cardiac arrest, stroke, and head trauma. Current research projects include investigation of: 1) the mechanism and consequences of disrupted calcium homeostasis in post-ischemic neurons, 2) the role of calpain and caspase proteolytic cascades in post-ischemic neuronal death, 3) optimizing therapeutic hypothermia after acute brain injury.
RESEARCH TECHNIQUES
Rodent model of global brain ischemia; immortalized and primary neuron culture and organotypic hippocampal slice culture models of acute neuronal injury; transient and stable gene transfection, vival vector gene therapy, Western blot, immunohistochemistry, histopathology, fluorescence microscopy, calcium imaging.
RESEARCH SUMMARY
Brain ischemia caused by cardiac arrest and stroke kills 300,000 people and disables another 150,000 each year in the United States. Other than early reperfusion, we have no clinically proven therapy to reduce post-ischemic brain damage. After an ischemic insult, neuronal death is delayed for hours to days. This interval represents a potential therapeutic window. The general goal of my research effort is to characterize the molecular events that cause delayed neuronal death after brain ischemia and develop clinically effective therapies to minimize brain damage after cardiac arrest and stroke.
The current research in my lab is focused on the molecular mechanisms of delayed neuronal death in post-ischemic neurons. Brain ischemia causes immediate intracellular Ca2+ overload that resolves within 1-2 hours of reperfusion. Subsequently, a secondary delayed disruption of Ca2+ homeostasis is observed which is temporally associated with the onset of delayed neuronal death. The mechanism of this secondary disruption of Ca2+ homeostasis remains unclear and potentially involves dysfunction of Ca2+ regulatory proteins in the plasma membrane, endoplasmic reticulum and mitochondria. Our experimental approach to this question involves functional analysis of Ca2+ regulatory proteins in post-ischemic neurons.
A second line of investigation involves analysis of proteolytic cascades in the post-ischemic neurons. Both calpain and caspase proteolytic pathways are activated in the brain after ischemia and reperfusion. While early investigations have linked caspases to apoptosis and calpains to necrosis, there is a growing body of evidence that signficant cross-talk occurs between these two pathways. Our work is focused on determining the causal role these and other proteolytic pathways play in delayed post-ischemic neuronal death. We have recently characterized the time course and location of both calpain and caspase activity in our model of transient global brain ischemia. Our current experimental approach involves biochemical and molecular manipulation of these proteolytic cascades.
Finally, we are exploring ways to optimize the application of therapeutic hypothermia after acute brain injury. Understanding optimal timing and duration of this therapy is fundamental to elucidating the causal mechanisms of neuroprotection.
Emergency Medicine
Selected Publications
Ma M, Li L, Wang X, Bull DL, Shofer FS, Meaney DF, Neumar RW: Short-Duration Treatment with the Calpain Inhibitor MDL-28170 Does Not Protect Axonal Transport in an in Vivo Model of Traumatic Axonal Injury. Journal of Neurotrauma 29(2): 445-51, Jan 2012.
Kopil CM, Vais H, Cheung KH, Siebert AP, Mak DO, Foskett JK, Neumar RW: Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) has InsP(3)-independent gating and disrupts intracellular Ca(2+) homeostasis. The Journal of Biological Chemistry 286(41): 35998-6010, Oct 2011.
Che D, Li Luchuan, Kopil CM, Liu Z, Guo W, Neumar RW: Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Critical Care Medicine 39(6): 1423-30, Jun 2011.
Bevers MB, Ingleton LP, Che D, Li L, Da T, Kopil CM, Cohen AS, Neumar RW.: RNAi targeting micro-calpain increases neuron survival and preserves hippocampal function after global brain ischemia. Exp Neurol 223(1): 170-177, Jul 2010.
von Reyn CR, Spaethling JM, Mesfin MN, Ma M, Neumar RW, Smith DH, Siman R, Meaney DF.: Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit. J Neurosci 29(33): 10350-10356, Aug 2009.
Gaieski DF, Band RA, Abella BS, Neumar RW, Fuchs BD,Kolansky DM; Merchant RM, Carr BG, Becker LB, Maguire C, Klair A, Hylton J, Goyal M.: Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest
Resuscitation 80(4): 418-24, Apr 2009.
Carr BG, Goyal M, Band RA, Gaiseki DF, Abella BS, Merchant RM, Branas CC, Becker LB, Neumar RW. : A national analysis of the relationship between hospital factors and post-cardiac arrest mortality. Int Care Med 35(3): 505-11, Mar 2009.
Bevers MB,. Lawrence E, Maronski M, Starr N, Amesquita M, Neumar RW
: Knockdown of m-calpain increases survival of primary hippocampal neurons following NMDA excitotoxicity
J. Neurochem 108(5): 1237-50, Mar 2009.
Carr BG, Kahn JM, Merchant RM, Kramer AA, Neumar RW: Inter-hospital variability in post-cardiac arrest mortality. Resuscitation 80(1): 30-4, Jan 2009.
Ma M, Matthews BT, Lampe JW, Meaney DF, Shofer FS, Neumar RW: Immediate short-duration hypothermia provides long-term protection in an in vivo model of traumatic axonal injury. Exp Neurol 215(1): 119-127, Jan 2009.
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Last updated: 02/07/2012
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