This is a competing continuation of a Bioengineering Research Partnership (BRP) grant focusing on the molecular mechanisms of traumatic brain injury (TBI). Our work in the last phase points out a potentially critical receptor - the calcium permeable AMPA receptor (CP-AMPAR) - that appears in neurons after mechanical injury and plays a key role in neuronal death. In the final phase of this BRP, we define the mechanisms regulating the appearance of CP-AMPARs (Aim 1), determine when CP-AMPAR activation leads to neuronal death (Aim 2), and develop therapies for reversing neuronal death initiated by CP- AMPARs (Aim 3). Our therapeutic approaches include strategies we can test immediately with available compounds, as well as new therapies developed with unique technologies to target key molecular events that lead to neuronal death. Our overlying hypotheses are (a) CP-AMPARs increase following injury due a change in the translation of AMPAR subunits, a change in the editing of GluR2 mRNA, and an ERK mediated insertion of GluR1 homomeric AMPARs. (b) Immediate or delayed inhibition of calcium permeable AMPARs reduce neuronal death after mechanical injury, and their effect is enhanced restoring G^luR2 editing (calpain inhibition) or inhibiting ERK phosphorylation, (c) Restoring ADAR2 editing activity of GluR2 mRNA, limiting the GluR2 synthesis, and interrupting Elk-1 signaling selectively in dendrites are effective delayed strategies to improve neuronal survival after injury. . We integrate the collective expertise of the BRP labs to test these hypotheses across the subcellular, cellular and organ scale. We evaluate transcription factor (Elk-1) signaling and the synthesis/regulation of CP- AMPAR subunits within individual dendrites after injury, measure changes in RNA editing and transcription within individual neurons and in slice culture, and test newly developed therapies in animal models of TBI. Relevance: This work studies factors that cause cell death after traumatic brain injury. The investigators test treatments to reduce neuronal death using commercially available compounds, and design new molecules that may be even more effective in reducing cell death. Both treatment approaches are tested for their effectiveness if given either immediately or several hours after injury, which is critical to know if these will be used clinically in the future.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041699-09
Application #
7891281
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Nitkin, Ralph M
Project Start
2001-08-03
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2010
Total Cost
$595,740
Indirect Cost
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Singh, Pallab; Doshi, Shachee; Spaethling, Jennifer M et al. (2012) N-methyl-D-aspartate receptor mechanosensitivity is governed by C terminus of NR2B subunit. J Biol Chem 287:4348-59
Spaethling, Jennifer; Le, Linda; Meaney, David F (2012) NMDA receptor mediated phosphorylation of GluR1 subunits contributes to the appearance of calcium-permeable AMPA receptors after mechanical stretch injury. Neurobiol Dis 46:646-54
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Singh, Pallab; Hockenberry, Adam J; Tiruvadi, Vineet R et al. (2011) Computational investigation of the changing patterns of subtype specific NMDA receptor activation during physiological glutamatergic neurotransmission. PLoS Comput Biol 7:e1002106
Creed, Jennifer A; DiLeonardi, Ann Mae; Fox, Douglas P et al. (2011) Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. J Neurotrauma 28:547-63
Saatman, Kathryn E; Creed, Jennifer; Raghupathi, Ramesh (2010) Calpain as a therapeutic target in traumatic brain injury. Neurotherapeutics 7:31-42

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