Role of cytochrome P450 reductase in Alzheimer's disease
细胞色素 P450 还原酶在阿尔茨海默病中的作用
基本信息
- 批准号:6956136
- 负责人:
- 金额:$ 5.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-08-01 至 2007-07-31
- 项目状态:已结题
- 来源:
- 关键词:Alzheimer&aposs diseaseNAD(P)H oxidoreductaseamyloid proteinsbehavior testbiomarkerbrain morphologycytochrome P450disease /disorder modelenzyme activityenzyme linked immunosorbent assayfree radical oxygengenetically modified animalsimmunocytochemistryin situ hybridizationlaboratory mousemodel design /developmentneuropathologyoxidative stresspathologic processphosphorylation
项目摘要
DESCRIPTION (provided by applicant): The objective is to determine the role of NADPH-cytochrome P450 reductase (CPR) in the pathogenesis of Alzheimer's disease (AD). The hypothesis is that CPR may contribute to the amyloid beta (A beta) protein-induced neuropathology in AD through its activities in the production of reactive oxygen species (ROS). CPR has long been known to be involved in ROS production. The current proposal for a 2-year, pilot study will focus on the development and characterization of an amyloid precursor protein (APP) transgenic mouse model with defective expression of CPR. This model will be generated by cross-breeding 2 existing single transgenic mice, 1 expressing transgenic APP and the other having greater than 75% decreases in the level of CPR expression throughout the major organs, including the brain. The latter mouse model has been generated in preliminary studies. The potential involvement of CPR in APP-induced neuropathology is supported by a recent finding on the induction of CPR proteins surrounding A beta deposits in the APP-transgenic mice and within the cortical neurons from the brains of human AD patients. Preliminary studies also indicated a decrease in the levels of amyloid plaques in the brains of APP mice with defective expression of CPR. Thus, a drastic decrease in CPR expression may lead to a significant reduction in A beta-mediated oxidative stress and alleviate neurodegenerative changes in AD. The new mouse model will be characterized to determine whether there will be a lower expression of markers of oxidative stress and a less extent of neuropathological and behavioral manifestations in the double transgenic mice than in the parental APP-transgenic mice. The outcome of this study could be the first direct evidence for the role of CPR in pathogenesis of AD in a transgenic mouse model. It will provide a better understanding of the molecular basis of pathogenesis of AD.
描述(由申请人提供):目的是确定NADPH-细胞色素P450还原酶(CPR)在阿尔茨海默病(AD)发病机制中的作用。假设CPR可能通过其活性氧(ROS)的产生促进淀粉样β(A β)蛋白诱导的AD神经病理学。CPR长期以来一直被认为参与ROS的产生。目前提出的为期2年的试点研究将集中于CPR表达缺陷的淀粉样前体蛋白(APP)转基因小鼠模型的开发和表征。该模型将通过杂交2只现有的单一转基因小鼠产生,1只表达转基因APP,另一只在整个主要器官(包括脑)中CPR表达水平降低大于75%。后一种小鼠模型已在初步研究中产生。CPR在APP诱导的神经病理学中的潜在参与得到了最近关于APP转基因小鼠中A β沉积物周围和人类AD患者大脑皮质神经元内CPR蛋白诱导的发现的支持。初步研究还表明,CPR表达缺陷的APP小鼠大脑中淀粉样蛋白斑块的水平降低。因此,CPR表达的急剧降低可能导致A β介导的氧化应激的显著降低并减轻AD中的神经退行性变化。将表征新的小鼠模型以确定双转基因小鼠中氧化应激标志物的表达是否低于亲本APP转基因小鼠,以及神经病理学和行为表现的程度是否低于亲本APP转基因小鼠。本研究的结果可能是CPR在转基因小鼠模型中AD发病机制中作用的第一个直接证据。这将有助于更好地了解AD发病机制的分子基础。
项目成果
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会议论文数量(0)
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{{ truncateString('JUN GU', 18)}}的其他基金
Role of local P450 enzymes in chemical carcinogenesis in mouse mammary gland
局部P450酶在小鼠乳腺化学癌变中的作用
- 批准号:
7870588 - 财政年份:2010
- 资助金额:
$ 5.65万 - 项目类别:
Role of local P450 enzymes in chemical carcinogenesis in mouse mammary gland
局部P450酶在小鼠乳腺化学癌变中的作用
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8063627 - 财政年份:2010
- 资助金额:
$ 5.65万 - 项目类别:
Role of cytochrome P450 reductase in Alzheimer's disease
细胞色素 P450 还原酶在阿尔茨海默病中的作用
- 批准号:
7097387 - 财政年份:2005
- 资助金额:
$ 5.65万 - 项目类别:
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