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NRF2 Anti-Oxidant Systems and White Matter Hyperintensities

NRF2 抗氧化系统和白质高信号

基本信息

批准号：
9256390
负责人：
Charles DeCarli
金额：
$ 61.24万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256390
关键词：
Age Alzheimer&apos s Disease Antioxidants Apoptosis Area Autopsy Binding Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Cell Nucleus Cerebrovascular Disorders Cessation of life Chronic Clinical Clinical Trials Cognitive Coupled Cytoplasm DNA Data Defense Mechanisms Development Distant Elderly Erythroid F2-Isoprostanes Future Gait Gene Expression Gene Targeting Genes Goals Health Human Hypertension Impaired cognition Impairment Individual Knock-out Knockout Mice Knowledge Lead Leukoencephalopathy Magnetic Resonance Imaging Measures Mental Depression Modeling Mutant Strains Mice Myelin Myelin Sheath NF-E2-related factor 2 Neuroglia Nuclear Oligodendroglia Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Patients Permeability Platelet Factor 4 Quantitative Reverse Transcriptase PCR Reactive Oxygen Species Response Elements Risk Risk Factors Role Signal Transduction Staining method Stains Stem cells Superoxide Dismutase System Therapeutic Intervention Time Vascular Diseases White Matter Hyperintensity age related aging population attenuation brain endothelial cell catalase cell killing cerebral hypoperfusion glutathione peroxidase improved in vivo myelin degeneration neuropathology novel oligodendrocyte progenitor oxidation prevent promoter public health relevance response therapeutic target treatment trial white matter

项目摘要

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.

描述（由申请人提供）：白色高信号（WMH）是T2和FLAIR脑MRI上的离散高信号强度区域。它们与年龄增长、血管疾病和其他因素有关，并导致认知能力下降、抑郁和步态障碍。由于WMH的累积可能会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，敲除Nrf 2（核因子红细胞衍生的2-样2）基因会导致脑髓鞘丢失，伴随着随着年龄的增长而发生的空泡性白质脑病。Nrf 2激活抗氧化反应元件（ARE）以调节下游抗氧化靶基因。这些发现，再加上我们的初步数据显示WMH患者血液中Nrf 2靶基因的表达增加，使我们将这项研究的重点放在Nrf 2上，并提出这些目标。目标1a：证明与远处未受影响的白色物质相比，WMH中通过尸检MRI识别的OLIGO和OPC数量减少。目标#1b。显示氧化应激标记物F2-异前列烷（髓鞘）和8-OH-2dG（DNA）在WMH中染色髓鞘和OLIGO核，而在远处未受影响的白色物质中无染色。目标1c。证明与远处未受影响的白色物质相比，WMH和WMH边缘的核Nrf 2蛋白和Nrf 2靶基因表达增加。目标2a：证明使用体内MRI测量的，与低容量WMH受试者相比，使用qRT-PCR测量的血液中Nrf 2靶基因的表达在大容量WMH受试者中增加。目标2b：证明与2年内WMH体积变化最小的匹配受试者相比，2年内WMH体积增加最多的受试者血液中使用qRT-PCR的Nrf 2靶基因表达持续升高或显著增加。目标3。证明从同一个体获得的血液和脑中存在目的#1和#2中的血液和WMH中的脑病理学变化和Nrf 2靶基因表达变化。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。系统性ROS损伤脑内皮细胞，允许促氧化剂分子进入脑，增加脑ROS，导致WMH。这项研究将开始，以确定新的Nrf 2治疗靶点，减少或预防WMH。它还将开始提供在进行抗氧化剂试验以减少WMH以延迟或预防认知能力下降之前所需的基本原理和初步数据。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early Brain Loss in Circuits Affected by Alzheimer's Disease is Predicted by Fornix Microstructure but may be Independent of Gray Matter.

DOI：
10.3389/fnagi.2014.00106
发表时间：
2014
期刊：
Frontiers in aging neuroscience
影响因子：
4.8
作者：
Fletcher E;Carmichael O;Pasternak O;Maier-Hein KH;DeCarli C
通讯作者：
DeCarli C

Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer's Disease Brain: A Review.

DOI：
10.3389/fnagi.2018.00042
发表时间：
2018
期刊：
Frontiers in aging neuroscience
影响因子：
4.8
作者：
Zhan X;Stamova B;Sharp FR
通讯作者：
Sharp FR

Amylin deposition in the brain: A second amyloid in Alzheimer disease?

DOI：
10.1002/ana.23956
发表时间：
2013-10
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Jackson, Kaleena;Barisone, Gustavo A.;Diaz, Elva;Jin, Lee-way;DeCarli, Charles;Despa, Florin
通讯作者：
Despa, Florin

Structural imaging measures of brain aging.