Peroxisome Proliferator-Activated Receptor and Stroke

描述(申请人提供中风是美国第三大死因和功能性残疾的主要原因。这一竞争性的R01更新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。贝特类是PPARa激动剂，已被用作调脂药物。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是有益的。在之前的资金周期中，我们发现两种贝特类药物非诺贝特和吉非罗齐显著改善了局灶性脑缺血后的脑血流，并减少了随后的脑梗塞范围。贝特类强效抑制脑部炎症。其疗效与其降脂效果无关，但需要PPARa的表达。基于这些发现，我们将进一步阐明PPARa激活与脑血管疗效之间的下游联系。我们正在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体。胞内异构体(SOD1)和胞外异构体(SOD3)都需要铜才能充分发挥活性。我们的初步研究表明，非诺贝特和吉非罗齐显著提高了大脑中SOD3的活性水平。此外，非诺贝特和吉非罗齐使铜伴侣蛋白SOD3、Atox1的mRNA水平升高。这些升高在PPARa基因缺失的小鼠中看不到。我们推测，Atox1通过PPARa的激活而升高，表明SOD3活性，这有助于贝特类药物对脑血管的保护作用。我们将在几个不同的突变株中使用具有良好特性的小鼠中风模型进行全面的实验。目的1是证明SOD3是非诺贝特保护脑血管的介质。目的2是证明Atox1在贝特类药物引起的SOD3升高和随后的脑血管保护中起作用。目的3是检测外周血细胞是否是PPARa-&GT；Atox1-&GT；SOD3轴激活的额外作用部位，从而导致脑血管保护。这项拟议的研究将提供第一个证据，证明Atox1可能是治疗缺血性中风的潜在靶点。所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.