NRF2 Anti-Oxidant Systems and White Matter Hyperintensities

描述(由申请人提供)： 白质高信号(WMH)是T2和FLAIR脑MRI上的离散高信号区域。它们与年龄增加、血管疾病和其他因素有关，并会导致认知能力下降、抑郁和步态障碍。由于WMH的增加可能随着血管危险因素的治疗而减少，因此有可能进行治疗干预。最近对突变小鼠的研究表明，Nrf2(核因子红系衍生2样蛋白)基因的敲除会导致脑髓鞘丢失，并伴随着随着年龄的增加而发生的空泡性白质脑病。NRF2激活抗氧化剂反应元件(ARE)来调节下游的抗氧化靶基因。这些发现，再加上我们的初步数据显示，WMH患者血液中Nrf2靶基因的表达增加，使我们将这项研究的重点放在Nrf2上，并提出了这些目标。目的#1a：证实WMH中死后MRI发现的寡核苷酸和OPC的数量与远处未受影响的白质相比减少。目标#1b。结果显示，氧化应激标志物F2-异前列腺素(髓鞘)和8-OH-2dG(DNA)在WMH中染色髓鞘和寡核，而在远处未受影响的白质中未染色。目标#1c。与远处未受影响的白质相比，WMH和WMH边缘的核Nrf2蛋白和Nrf2靶基因表达增加。目的#2a：通过体内MRI检测，证实大容量WMH患者血液中Nrf2靶基因的表达水平高于低容量WMH患者。目的#2b：证明与WMH体积变化最小的匹配受试者相比，两年以上WMH体积增加最多的受试者血液中Nrf2靶基因的表达要么持续升高，要么显著增加。目的#3.证明AIMS#1和AIMS#2中血液和WMH中的脑病理改变和Nrf2靶基因表达的变化存在于同一个体的血液和脑中。在这项研究中，我们将确定全身和大脑氧化应激是否与WMH损伤、大WMH体积和WMH体积随时间的进展相关。全身性ROS损伤大脑内皮细胞，使促氧化剂分子进入大脑，从而增加大脑ROS，从而导致WMH。这项研究将开始寻找新的Nrf2治疗靶点，以减少或预防WMH。它还将开始提供抗氧化剂试验之前所需的理论基础和初步数据，以减少WMH，目的是延缓或防止认知能力下降。

DESCRIPTION (provided by applicant): White Matter Hyperintensities (WMH) are areas of discrete high signal intensity on T2 and FLAIR brain MRI. They are associated with increasing age, vascular disease and other factors and cause cognitive decline, depression and gait impairment. Since accrual of WMH may diminish with treatment of vascular risk factors, there is a potential for therapeutic intervention Recent studies of mutant mice show that knockout of the Nrf2 (Nuclear factor erythroid-derived 2-like 2) gene results in loss of brain myelin with a vacuolar leukoencephalopathy that occurs with advancing age. Nrf2 activates antioxidant response elements (ARE) to modulate downstream anti-oxidant target genes. These findings, coupled with our preliminary data showing increased expression of Nrf2 target genes in the blood of patients with WMH, has led us to focus this study on Nrf2 and propose these aims. Aim #1a: Demonstrate that the number of OLIGOs and OPCs in WMH identified by post-mortem MRI are decreased in WMH compared to distant unaffected white matter. Aim# 1b. Show that markers of oxidative stress, F2-isoprostane (myelin) and 8-OH-2dG (DNA), stain myelin sheaths and OLIGO nuclei in WMH compared to no staining in distant unaffected white matter. Aim# 1c. Demonstrate increased nuclear Nrf2 protein and increased Nrf2 target gene expression in WMH and at the margins of WMH as compared to distant unaffected white matter. Aim #2a: Demonstrate that expression of Nrf2 target genes in blood using qRT-PCR is increased in subjects with large volume WMH compared to those with low volume WMH as measured using in vivo MRI. Aim# 2b: Demonstrate that the expression of Nrf2 target genes using qRT-PCR is either persistently elevated or markedly increases in blood of subjects whose WMH volumes increase the most over 2 years compared to matched subjects who have the smallest changes in WMH volumes over 2 years. Aim #3. Demonstrate that brain pathological changes and Nrf2 target gene expression changes in blood and WMH in Aims #1 and #2 are present in the blood and brain obtained from the same individual. In this study we will determine whether systemic and brain oxidative stress correlate with WMH damage, large WMH volumes and progression of WMH volumes over time. Systemic ROS damage brain endothelial cells allowing pro-oxidant molecules into brain that increase brain ROS that contribute to WMH. This study will begin to identify novel Nrf2 therapeutic targets for decreasing or preventing WMH. It will also begin to provide the rationale and preliminary data needed before antioxidant trials would be undertaken to reduce WMH with the goal of delaying or preventing cognitive decline.