This is a revised competing continuation of a grant focusing on the biomechanics of traumatic brain injury. In this continuation application, we study how tissue strains translate to cellular strains in the hippocampus, and proceed to concentrate on the NMDA receptor (NMDAR) mechanosensitivity and its role in hippocampal neuronal death. The broad, long term objective is to examine if regional neuronal populations are 'mechanically vulnerable'and susceptible to injury, to test if extrasynpatic and synpatic NMDARs have different mechanosensitivity, and to use the data on NMDAR mechanosensitivity to evaluate both immediate and delayed treatment strategies to reduce neuronal death after mechanical injury.
The specific aims of this research plan are as follows:
Aim 1 : To describe the local micromechanical environment in organotypic hippocampal cultures subjected to realistic, in vivo deformations associated with injury.
Aim 2 : To measure the mechanoactivation threshold for extrasynaptic and synaptic NMDAR using recombinant NMDAR expressed in HEK293t cells and organotypic hippocampal cultures.
Aim 3 : To examine the activation and control of both JNK and ERK from mechanosensitive NMDARs, using this information to examine acute and delayed treatment strategies for reducing cell death after mechanical injury. Our overlying hypotheses are (a) at the same level of tissue stretch, neurons in the dentate gyrus and CAS experience higher mechanical deformations than other hippocampal regions, (b) NMDARs are stretch sensitive due to linkages to the cytoskeleton, (c) the mechanoactivation of extrasynaptic NMDA receptors will influence the activation of JNK through STEP, and (d) ERK activation will be preferentially controlled by synaptic NMDARs, with the duration of ERK signaling mediated by the activity of STEP. Relevance: This work will study how neurons in the hippocampus are injured during traumatic brain injury. The work will concentrate on studying the mechanical activation of a receptor known to play a role in memory formation and cell death. Using the information of receptor activation, the investigators will develop and test treatment strategies to reduce neuronal death following traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035712-13
Application #
7758753
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
1997-05-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2010
Total Cost
$368,213
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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Choo, Anthony M; Miller, William J; Chen, Yung-Chia et al. (2013) Antagonism of purinergic signalling improves recovery from traumatic brain injury. Brain 136:65-80
Mesfin, Mahlet N; von Reyn, Catherine R; Mott, Rosalind E et al. (2012) In vitro stretch injury induces time- and severity-dependent alterations of STEP phosphorylation and proteolysis in neurons. J Neurotrauma 29:1982-98
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
von Reyn, Catherine R; Mott, Rosalind E; Siman, Robert et al. (2012) Mechanisms of calpain mediated proteolysis of voltage gated sodium channel ?-subunits following in vitro dynamic stretch injury. J Neurochem 121:793-805
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
Choo, Anthony M; Geddes-Klein, Donna M; Hockenberry, Adam et al. (2012) NR2A and NR2B subunits differentially mediate MAP kinase signaling and mitochondrial morphology following excitotoxic insult. Neurochem Int 60:506-16
Meaney, David F; Smith, Douglas H (2011) Biomechanics of concussion. Clin Sports Med 30:19-31, vii
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
von Reyn, Catherine R; Spaethling, Jennifer M; Mesfin, Mahlet N et al. (2009) Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit. J Neurosci 29:10350-6

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