Despite recent advances in the treatment and prevention of cardiovascular disease, stroke remains the third leading cause of death and a leading cause of serious, long-term disability in US. Therapeutic strategies aimed at minimizing the deleterious effects of ischemia on neurons once stroke takes place are still lacking, and clinical trials using neuroprotective agents have largely failed. We uncovered an endogenous mechanism of neuroprotection, whereby neurons respond to ischemia by increasing the number of peroxisomes, highly adaptable small organelles that contribute to neuronal survival by enhancing neuronal cell antioxidant capacity and the ability to cope with metabolic stress during ischemia-reperfusion. The proposed project will use both in vivo and in vitro models of ischemic neural injury to determine if peroxisomal proliferation is increased in neurons after ischemia by the translocation to peroxisomes of an otherwise cytosolic enzyme called soluble epoxide hydrolase (sEH).
Aim 1 will determine if sEH translocation requires binding of its peroxisome-targeting signal-1 (PTS-1), located on the C-terminal, to the peroxisomal shuttle protein peroxin 5 (PEX5).
Aim 2 will determine if sEH translocation contributes to peroxisomal proliferation, which plays a neuroprotective role after cerebral ischemia.
Aim 3 will determine if increased peroxisomal density after cerebral ischemia is mediated though a dual action of sEH to promote peroxisomal biogenesis and suppress peroxisomal degradation. The proposed research is highly significant and innovative both technically and conceptually. Peroxisomal biogenesis has not been previously described in brain after cerebral ischemia, and a role for sEH in this process has not been investigated. If confirmed, the proposed studies will pave the way for a new line of research focusing on peroxisomal biogenesis after stroke, and may lead to the development of novel therapeutic agents for stroke based on promoting peroxisomal translocation of sEH and enhancing the endogenous neuroprotective response to increase peroxisomal biogenesis and prevent their degradation.

Public Health Relevance

The proposed research is aimed at understanding how small organelles called peroxisomes increase in number to protect neurons from stroke. The results will pave the way for the development of new therapeutic agents for stroke based on simulating and enhancing this endogenous neuronal response to injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044313-12
Application #
8232042
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2002-06-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$409,664
Indirect Cost
$127,533
Name
Oregon Health and Science University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Nelson, Jonathan W; Das, Anjali J; Barnes, Anthony P et al. (2016) Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes. PLoS One 11:e0152742
Jia, Jia; Davis, Catherine M; Zhang, Wenri et al. (2016) Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium. Exp Neurol 279:75-85
Zhu, Wenbin; Casper, Amanda; Libal, Nicole L et al. (2015) Preclinical evaluation of recombinant T cell receptor ligand RTL1000 as a therapeutic agent in ischemic stroke. Transl Stroke Res 6:60-8
Zhu, W; Dotson, A L; Libal, N L et al. (2015) Recombinant T-cell receptor ligand RTL1000 limits inflammation and decreases infarct size after experimental ischemic stroke in middle-aged mice. Neuroscience 288:112-9
Siler, Dominic A; Martini, Ross P; Ward, Jonathan P et al. (2015) Protective role of p450 epoxyeicosanoids in subarachnoid hemorrhage. Neurocrit Care 22:306-19
Young, Jennifer M; Nelson, Jonathan W; Cheng, Jian et al. (2015) Peroxisomal biogenesis in ischemic brain. Antioxid Redox Signal 22:109-20
Nelson, Jonathan W; Zhang, Wenri; Alkayed, Nabil J et al. (2015) Peroxisomal translocation of soluble epoxide hydrolase protects against ischemic stroke injury. J Cereb Blood Flow Metab 35:1416-20
Zuloaga, Kristen L; Krasnow, Stephanie M; Zhu, Xinxia et al. (2014) Mechanism of protection by soluble epoxide hydrolase inhibition in type 2 diabetic stroke. PLoS One 9:e97529
Zhu, Wenbin; Libal, Nicole L; Casper, Amanda et al. (2014) Recombinant T cell receptor ligand treatment improves neurological outcome in the presence of tissue plasminogen activator in experimental ischemic stroke. Transl Stroke Res 5:612-7
Nelson, Jonathan W; Young, Jennifer M; Borkar, Rohan N et al. (2014) Role of soluble epoxide hydrolase in age-related vascular cognitive decline. Prostaglandins Other Lipid Mediat 113-115:30-7

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