The endoplasmic reticulum (ER) stress response (ERSR) is one of the major defense mechanisms that protect against cellular insult but if unchecked leads to apoptotic cell death. The ERSR has three arms initiated by PERK, IRE1, ATF6, respectively. Preliminary data show the acute activation of all three ERSR signaling pathways in endothelial cells (ECs) after SCI. Most importantly, we show that attenuation of PERK signaling in CHOP-/- (the downstream effector of PERK) mice or after i.v. salubrinal (which sustains protein synthesis inhibition) leads to enhanced functional recovery after SCI in WT mice. We found an acute vasoconstrictive phase following SCI and can enhance EC protection by the vasodilator nimodipine plus the vasoprotector glibenclamide in WT mice. Specifically, Aim 1 will delineate the specific effectors that underlie ERSR-mediated EC death by PERK signaling. We will determine if reducing PERK or ATF4 signaling in ECs after SCI will enhance functional recovery after SCI. This will be done using available transgenic mice (Aim 1a) and siRNA methods (Aim 1b). We hypothesize that the earlier in the ERSR pathway that inhibition occurs, the more extensive the vasoprotection and recovery.
Aim 2 will characterize the acute activation profile of the ERSR in FACS purified ECs when one signaling pathway is deleted (Aim 2a), their effects on spinal cord microvasculature (Aim 2b) and the functional consequences (Aim 2c).
Aim 3 will test whether EC rescue by ER stress inhibitors can be improved when combined with the vasodilators, nimodipine or MgSO4, the mainstay treatments for CNS vasospasm.
Aim 3 a will optimize vasodilation protocols.
Aim 3 b will optimize treatment regimens for salubrinal and two chemical chaperones that influence ERSR signaling: TUDCA (in clinical trials for ALS) and PBA (FDA-approved). We will then test whether optimized vasodilation would further improve the efficacy of those drugs using both pharmacological and genetic approaches.
Aim 3 c will define determine the therapeutic window. Collectively, the experiments outlined in these 3 Aims delineate a strategy to optimally inhibit ER stress in ECs to maximize functional recovery after SCI and determine whether this approach is clinically relevant.

Public Health Relevance

This grant examines the role of the endoplasmic reticulum stress response, a cellular defense mechanism induced in every spinal cord cell after SCI, which, if unchecked, leads to cell loss after SCI causing the loss of neurological functions. Our previous data show the crucial role of endothelial cell death of blood vessels in the spinal cord in the ensuing secondary loss of spinal cord tissue. Using both genetic approaches and current FDA approved and/or in clinical trial drugs to rescue the endothelial cells, we expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-W (02))
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Jakeman, Lyn B
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University of Louisville
Schools of Medicine
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Myers, Scott A; Andres, Kariena R; Hagg, Theo et al. (2014) CD36 deletion improves recovery from spinal cord injury. Exp Neurol 256:25-38
Nielson, Jessica L; Guandique, Cristian F; Liu, Aiwen W et al. (2014) Development of a database for translational spinal cord injury research. J Neurotrauma 31:1789-99
Muradov, Johongir M; Ewan, Eric E; Hagg, Theo (2013) Dorsal column sensory axons degenerate due to impaired microvascular perfusion after spinal cord injury in rats. Exp Neurol 249:59-73
Muradov, Johongir M; Hagg, Theo (2013) Intravenous infusion of magnesium chloride improves epicenter blood flow during the acute stage of contusive spinal cord injury in rats. J Neurotrauma 30:840-52
Myers, Scott A; DeVries, William H; Gruenthal, Mark J et al. (2012) Sildenafil improves epicenter vascular perfusion but not hindlimb functional recovery after contusive spinal cord injury in mice. J Neurotrauma 29:528-38
Myers, Scott A; DeVries, William H; Andres, Kariena R et al. (2011) CD47 knockout mice exhibit improved recovery from spinal cord injury. Neurobiol Dis 42:21-34
Fassbender, Janelle M; Myers, Scott A; Whittemore, Scott R (2011) Activating Notch signaling post-SCI modulates angiogenesis in penumbral vascular beds but does not improve hindlimb locomotor recovery. Exp Neurol 227:302-13
Fassbender, Janelle M; Whittemore, Scott R; Hagg, Theo (2011) Targeting microvasculature for neuroprotection after SCI. Neurotherapeutics 8:240-51
Arnold, Sheila A; Hagg, Theo (2011) Anti-inflammatory treatments during the chronic phase of spinal cord injury improve locomotor function in adult mice. J Neurotrauma 28:1995-2002
Mozer, Anthony B; Whittemore, Scott R; Benton, Richard L (2010) Spinal microvascular expression of PV-1 is associated with inflammation, perivascular astrocyte loss, and diminished EC glucose transport potential in acute SCI. Curr Neurovasc Res 7:238-50

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