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Gene-based TNF-alpha activity modulation in 3xTg-AD mice

Gene-based TNF-alpha activity modulation in 3xTg-AD mice
3xTg-AD 小鼠中基于基因的 TNF-α 活性调节
批准号:
8048981
负责人:
WILLIAM J. BOWERS
金额:
$26.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-04-01 至 2011-10-08

项目摘要

项目成果

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中文摘要
翻译
描述(由申请人提供):阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病,与进行性功能下降、痴呆和神经元丧失相关,影响约40%的85岁以上人群。人口统计数据表明,随着世界人口年龄中位数的增加,阿尔茨海默病的患病率和社会经济负担将大幅增加。该疾病的病理标志包括β淀粉样蛋白(A3)斑块和神经原纤维缠结,它们在阿尔茨海默病的发病机制中起着关键作用,具有时间和空间的演变。我们感兴趣的是了解导致或延续这种AD发病机制的时间和空间进展的早期机制。炎症过程被认为是在大脑内启动和/或传播AD相关病理的组成部分,因为炎症细胞因子表达和其他炎症标志物的细化在已知AD病理的个体中更为明显。最近,一种同时发生淀粉样蛋白和tau蛋白病理的3xTg-AD小鼠AD模型已经被创建,这是迄今为止描述人类阿尔茨海默病发生的最相关的疾病模型系统。我们观察到在明显淀粉样蛋白病理发生之前,该模型中促炎细胞因子TNF-a的显著上调。由于TNF-a已被证明在轻度认知障碍和阿尔茨海默病患者中增强,3xTg-AD小鼠为研究该细胞因子在疾病早期阶段的作用提供了一个新的范例。我们假设TNF-a介导的炎症使AD模型中存在淀粉样蛋白和tau病变的遗传易感性,并且抑制这种炎症反应将减少病理性淀粉样蛋白和tau的结果。此外,我们假设炎症事件发生前的局灶性诱导将以区域和时间的方式加剧病理结果。我们将使用表达TNF-a的重组腺相关病毒(rAAV)载体来产生持续的局灶炎症反应,或者在现有病理之前使用TNF受体拮抗剂来抑制内源性炎症反应。这项工作将为炎症参与早期阿尔茨海默病致病事件的时间和空间进展提供重要见解,并可能阐明新的治疗靶点。
英文摘要
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive functional decline, dementia and neuronal loss affecting approximately 40 percent of persons over the age of 85 years. The demographics make evident that as the median age of the world's population increases, the prevalence and socioeconomic burden of AD will increase substantially. Pathological hallmarks of the disease include amyloid beta (A3) plaques and neurofibrillary tangles, which play a key role in the pathogenic mechanism of Alzheimer's disease, evolving in a temporal and spatial manner. We are interested in understanding the early mechanisms that cause or perpetuate this temporal and spatial progression of AD pathogenesis. Inflammatory processes have been proposed as being integral for initiating and/or propagating AD-associated pathology within the brain, as the elaboration of inflammatory cytokine expression and other markers of inflammation is more pronounced in individuals with known AD pathology. Recently, a 3xTg-AD mouse model of AD that develops both amyloid and tau pathology has been created, which to date is the most disease-relevant model system depicting what occurs in human Alzheimer's disease. We have observed significant up-regulation of the pro-inflammatory cytokine TNF-a in this model prior to the onset of overt amyloid pathology. As TNF-a has been shown to be enhanced in persons with mild cognitive impairment and Alzheimer's disease, the 3xTg-AD mouse provides a novel paradigm in which to investigate the role of this cytokine during early disease stages. We hypothesize that TNF-a mediated inflammation perpetuates disease in an AD model where genetic predisposition to amyloid and tau pathologies exist and that dampening this inflammatory response will diminish the pathological amyloid and tau outcome. Additionally, we hypothesize that the focal induction of an inflammatory event prior to the onset of inflammation will exacerbate pathological outcomes in a regional and temporal manner. We will administer recombinant adeno-associated virus (rAAV) vectors expressing either TNF-a to create a sustained focal inflammatory response or a TNF receptor antagonist to inhibit the endogenous inflammatory response prior to existing pathology. This work will provide major insight into the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially elucidate new therapeutic targets.
期刊论文(1)
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DOI: 10.1016/j.cellsig.2010.01.010
发表时间: 2010-07
期刊: Cellular signalling
影响因子: 4.8
作者: [Park KM, Bowers WJ]
通讯作者: Bowers WJ
scFv-based Abeta Oligomer Targeting in 3xTg-AD Mice
  • 批准号:
    7777857
  • 项目类别:
  • 资助金额:
    $16.13万
  • 财政年份:
    2009
  • 负责人:
    WILLIAM J. BOWERS
  • 依托单位:
Gene-based TNF-alpha activity modulation in 3xTg-AD mice
  • 批准号:
    7208146
  • 项目类别:
  • 资助金额:
    $27.41万
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    2007
  • 负责人:
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  • 依托单位:
Gene-based TNF-alpha activity modulation in 3xTg-AD mice
  • 批准号:
    7796627
  • 项目类别:
  • 资助金额:
    $27.57万
  • 财政年份:
    2007
  • 负责人:
    WILLIAM J. BOWERS
  • 依托单位:
Gene-based TNF-alpha activity modulation in 3xTg-AD mice
  • 批准号:
    7596413
  • 项目类别:
  • 资助金额:
    $27.84万
  • 财政年份:
    2007
  • 负责人:
    WILLIAM J. BOWERS
  • 依托单位:
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