My goal is to find a treatment for stroke and CNS injury. Such injuries are partly mediated by synaptic glutamate receptors, which are also essential for CNS function. Curtailing synaptic function with glutamate antagonists is harmful and is a failed approach to treating stroke in humans. We have shown that toxic glutamatergic signals are restricted to distinct pathways, indicating that they might be blocked selectively, without affecting essential synaptic activity. This grant pursues our discovery of the molecular mechanism for neurotoxic signaling, which depends on NMDA receptor (NMDAR) interactions with submembrane scaffolding proteins. A key interaction is that of NMDARs with the scaffolding protein PSD-95. We have suppressed neuronal PSD-95, which uncoupled NMDARs from nitric oxide synthase, an enzyme tethered to NMDARs by PSD-95. This blocked NMDAR toxicity without blocking synaptic activity. More recently, using cell-permeant peptides that disrupt NMDAR/PSD-95 coupling, we treated stroke in animals. The treatment reduced focal ischemic brain damage in rats and improved their neurological outcome without blocking synaptic function. Our approach avoids the negative consequences of blocking NMDARs and may constitute a practical stroke therapy. We propose to pursue this promising approach further.
In AIM 1 we will determine the mechanism of action of the therapeutic molecules that we discovered.
In AIM 2 we will focus on the therapeutic limits (therapeutic window, duration of effect, neurobehavioral consequences) and toxicity of treating stroke and CNS trauma by dissociating NMDAR/ PSD-95 interactions.
In AIM 3 we will identify novel therapeutic targets for neurological disease based on downstream interactions of PSD-95. The results will provide knowledge on mechanisms of disease and synaptic function, and validate a stroke treatment with the future intention of proceeding to human trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048956-04
Application #
7263085
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Hicks, Ramona R
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$233,300
Indirect Cost
Name
University Health Network
Department
Type
DUNS #
208469486
City
Toronto
State
ON
Country
Canada
Zip Code
M5 2-M9
Sun, Hong-Shuo; Jackson, Michael F; Martin, Loren J et al. (2009) Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nat Neurosci 12:1300-7
Soriano, Francesc X; Martel, Marc-Andre; Papadia, Sofia et al. (2008) Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. J Neurosci 28:10696-710
Sun, Hong-Shuo; Doucette, Tracy A; Liu, Yitao et al. (2008) Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 39:2544-53
Cui, Hong; Hayashi, Amy; Sun, Hong-Shuo et al. (2007) PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci 27:9901-15
Lau, Anthony; Arundine, Mark; Sun, Hong-Shuo et al. (2006) Inhibition of caspase-mediated apoptosis by peroxynitrite in traumatic brain injury. J Neurosci 26:11540-53
Arundine, Mark; Aarts, Michelle; Lau, Anthony et al. (2004) Vulnerability of central neurons to secondary insults after in vitro mechanical stretch. J Neurosci 24:8106-23