Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily (TNFSF) that acts on responsive cells via binding to a cell surface receptor known as fibroblast growth factor-inducible 14 (Fn14). TWEAK and Fn14 expression has been detected under non-ischemic conditions in neurons, and either middle cerebral artery occlusion (MCAO) or exposure of neuronal cultures to oxygen-glucose deprivation (OGD) conditions results in a significant increase in the expression of this cytokine and its receptor. We have demonstrated that the binding of TWEAK to Fn14 induces NF-?B activation and neuronal cell death and that inhibition of TWEAK activity following MCAO either by treatment with a soluble Fn14-Fc decoy receptor or genetic deficiency of Fn14 decreases the volume of the ischemic lesion and protects the area of ischemia penumbra. In this proposal we hypothesize that the interaction between TWEAK and Fn14 during cerebral ischemia induces neuronal cell death in the area of ischemic penumbra via caspase- dependent and -independent mechanisms. More specifically, we postulate that the binding of TWEAK to Fn14 following MCAO induces cell death by activation of the "intrinsic" and "extrinsic" apoptotic pathways, as well as by NF-?B-dependent activation of poly(ADP-ribose) polymerase-1 (PARP-1) with nuclear translocation of the apoptosis-inducing factor (AIF). Moreover, treatment with inhibitors of TWEAK activity after MCAO decreases cerebral ischemia-induced neuronal death and improves the fate of the ischemic tissue as evaluated by in vivo state-of-the-art neuroimaging techniques. These are clinically-relevant studies likely to result in a new therapeutic approach to prevent neuronal cell death in patients with ischemic stroke.

Public Health Relevance

Early after the onset of ischemic stroke there is an increase in the expression of the cytokine TWEAK and its receptor Fn14. The binding of TWEAK to Fn14 induces neuronal death. This application focuses on the study of the mechanism whereby TWEAK induces cell death and the use of inhibitors of TWEAK activity as a potential therapeutic strategy to prevent neuronal death during acute ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062073-04
Application #
8231384
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2009-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$330,138
Indirect Cost
$94,325
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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