Peroxisome Proliferator-Activated Receptor and Stroke

中风是美国第三大死亡原因，也是功能性残疾的主要原因。这项竞争性的R01更新申请要求5年的支持，以发现一种新的治疗缺血性中风的靶点。贝特类是过氧化物酶体增殖激活受体α (PPARa)激动剂，已被规定为血脂正常化药物。最近的实验证据表明，贝特类药物对包括缺血性中风在内的神经系统疾病有益。在之前的资助周期中，我们发现两种贝特类药物，非诺贝特和吉非罗齐，显著改善小鼠局灶性缺血后的脑血流量，并减少随后的梗死面积。贝特类药物能有效抑制脑部炎症。这些功效与降脂作用无关，但需要PPARa的表达。基于这些发现，我们将进一步阐明PPARa激活与脑血管疗效的下游联系。我们重点关注铜伴侣蛋白和超氧化物歧化酶（SOD）作为脑血管疗效的介质。细胞质异构体（SOD1）和细胞外异构体（SOD3）都需要铜才能充分发挥其活性。我们的初步研究表明，非诺贝特和吉非罗齐能显著提高大脑中SOD3的活性水平。此外，非诺贝特和吉非非齐可提高铜伴侣SOD3、Atox1 mRNA水平。在PPARa缺失小鼠中未见这种升高。我们假设PPARa激活引起的Atox1升高与SOD3活性有关，SOD3活性有助于贝特类药物对脑血管的保护。我们将在几种不同的突变株中使用具有良好特征的小鼠中风模型进行综合实验。目的1是证明SOD3作为非诺贝特脑血管保护的介质。目的2是证明Atox1有助于SOD3升高和随后贝特类药物的脑血管保护。目的3：检测外周血细胞是否为PPARa -> Atox1 -> SOD3轴激活的附加作用位点，从而起到脑血管保护作用。这项研究将首次证明Atox1可能是缺血性卒中的潜在治疗靶点。获得的知识将增加我们对铜贩运在脑血管疾病中的重要性的理解。

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.