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Robert
W. Neumar, M.D., Ph.D.
Associate Professor of Emergency Medicine
School of Medicine
313A Stellar-Chance
(215) 898-4960 FAX: (215) 573-5140
email: neumarr@uphs.upenn.edu
Website: http://www.med.upenn.edu/neumarlab
Click here for selected publications since Dr. Neumar's arrival at Penn
RESEARCH INTERESTS
Mechanisms of neuronal injury after cardiac arrest and stroke. 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. RESEARCH TECHNIQUES
Rodent model of global brain ischemia; immortalized and primary neuron culture models of acute neuronal injury; transient and stable gene transfection, 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 coupled with direct measurement of subcellular Ca2+ concentrations using x-ray diffraction microanalysis.
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.
The Neumar Lab
