Peroxisome Proliferator-Activated Receptor and Stroke

描述（由申请人提供 中风是美国第三大死亡原因，也是功能障碍的主要原因。这项竞争性 R01 续展申请需要五年的支持，以发现针对缺血性中风的新治疗靶点。贝特类药物是过氧化物酶体增殖物激活受体 α (PPARa) 激动剂，已被用作脂质正常化药物。最近的实验证据表明，贝特类药物有益于治疗包括缺血性中风在内的神经系统疾病。在上一个资助周期中，我们证明了两个贝特类、非诺贝特和吉非贝齐显着改善了小鼠局灶性缺血后的脑血流量，并减少了随后的梗塞面积，其功效与其降脂作用无关，但需要 PPARa 表达。基于这些发现，我们将进一步阐明 PPARa 激活与脑血管功效的下游联系。我们的初步研究表明，非诺贝特和吉非贝齐可显着提高大脑中 SOD3 的活性水平。假设 PPARa 激活引起的 Atox1 升高表明 SOD3 活性，这有助于贝特类药物的脑血管保护。目标 1 是证明 SOD3 作为非诺贝特的脑血管保护作用的介质。目标 2 是证明 Atox1 有助于贝特类药物的脑血管保护。三是测试外周血细胞是否是 PPARa -> Atox1 -> SOD3 轴激活导致脑血管保护的额外作用位点。这项研究将提供 Atox1 可能是对抗缺血性中风的潜在治疗靶点的第一个证据。所获得的知识将增加我们对铜转运在脑血管疾病中的重要性的认识。

DESCRIPTION (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.