(provided by applicant Stroke is the third leading cause of death and the primary cause of functional disability in the United States. This competitive R01 renewal application requests five years of support to discover a novel therapeutic target against ischemic stroke. Fibrates are peroxisome proliferator-activated receptor alpha (PPARa) agonists and have been prescribed as lipid normalizing drugs. Recent experimental evidence suggests that fibrates are beneficial against neurological diseases including ischemic stroke. In the previous funding cycle, we showed that two fibrates, fenofibrate and gemfibrozil, significantly improved cerebral blood flow after focal ischemia and reduced subsequent infarct size in mice. Fibrates strongly inhibited brain inflammation. The efficacies were independent of their lipid lowering effects but required PPARa expression. Based on these findings, we will further elucidate the downstream linking of PPARa activation to the cerebrovascular efficacies. We are focusing on copper chaperone proteins and superoxide dismutase (SOD) as the mediators of the cerebrovascular efficacies. Both cytosolic isoform (SOD1) and extracellular isoform (SOD3) require copper for their full activity. Our preliminary study showed that fenofibrate and gemfibrozil strongly elevated SOD3 activity levels in the brain. In addition, fenofibrate and gemfibrozil elevated copper chaperone for SOD3, Atox1 mRNA level. These elevations were not seen in PPARa null mice. We hypothesize that Atox1 elevation by PPARa activation pronounces SOD3 activity, which contributes to the cerebrovascular protection by fibrates. We will conduct comprehensive experiments using a well characterized mouse stroke model in several different mutant strains. Aim 1 is to demonstrate SOD3 as a mediator of cerebrovascular protection by fenofibrate. Aim 2 is to demonstrate that Atox1 contributes to the SOD3 elevation and subsequent cerebrovascular protection by fibrates. Aim 3 is to test whether or not peripheral blood cells are additional action sites for the PPARa -> Atox1 -> SOD3 axis activation to lead to the cerebrovascular protection. The proposed study will provide the first evidence that Atox1 may be a potential therapeutic target against ischemic stroke. Obtained knowledge will increase our understanding about the importance of copper trafficking in cerebrovascular diseases.

R01NS048532

2004-04-01

2015-03-31