ANTIOXIDANT/ELECTROPHILE RESPONSE GENES IN NEUROTOXICITY

神经毒性中的抗氧化剂/亲电反应基因

• 批准号: 6635496
• 负责人: Jeffrey A Johnson
• 金额: $ 34.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635496
• 关键词: Alzheimer's disease; NAD(P)H dehydrogenase; amyloid proteins; antioxidants; apoptosis; brain cell; clinical research; gene expression; genetic regulation; genetically modified animals; histochemistry /cytochemistry; human tissue; hydroquinones; intermolecular interaction; laboratory mouse; molecular dynamics; neuroblastoma; neurotoxicology; oxidative stress; phosphorylation; protein kinase; regulatory gene; tissue /cell culture; western blottings

DESCRIPTION: (ADAPTED FROM APPLICANT'S ABSTRACT) Induction of NAD(P)H:quinone oxidoreductase (QR) by tert-butylhydroquinone (tBHQ) prior to glutamate treatment significantly decreased glutamate-mediated cytotoxicity. Stable overexpression of QR, however, did not protect cells from glutamate-, dopamine or H2O2-induced apoptosis. Thus, the protection afforded by tBHQ is not due simply to an increase in QR, but the coordinate regulation of multiple genes by a common mechanism. Our laboratory has shown that tBHQ increases QR through activation of its antioxidant response element (ARE) in human neuroblastoma cells and primary glial cell cultures. We hypothesize that increased expression of ARE-driven genes block oxidative stress-induced cell death. The specific aims of this proposal are to: 1) Determine the molecular mechanism(s) by which tBHQ activates the ARE and increases QR in human neuroblstoma cells; 2) Characterize the expression pattern and regulation of the ARE in vivo; 3) Determine the effect of overexpresion of amyloid precursor protein on QR and ARE in transgenic mouse models of alzheimer's disease; 4) Characterize the expression pattern of QR in human brains from control and AD patients. Increased oxidative stress is associated with neuronal cell death following acute insults such as epilepsy, ischemia, and hypoglycemia. Oxidative stress is also believed to be a principle factor in the development of many chronic neurodegenerative diseases such as Alzheimer's, Parkinson's Huntington's and Amyotrophic Lateral Sclerosis. Oxidative stress is an imbalance in which free radicals and their products exceed the capacity of antioxidant defense mechanisms. A gain in product formation and /or loss in protective mechanisms can disturb this equilibrium. Presently, we have little knowledge of how or by neurodegenerative diseases such as Alzheimer's disease (Specific Aims 3 and 4). Elucidating the molecular mechanisms (s) regulating ARE genes in brain, therefore, may be crucial for developing therapeutic approaches to mitigate, or prevent, neurotoxicity.

描述：（改编自申请人的摘要）NAD(P)H:醌的诱导 在谷氨酸之前通过叔丁基氢醌 (tBHQ) 进行氧化还原酶 (QR) 治疗显着降低了谷氨酸介导的细胞毒性。稳定的 然而，QR 的过度表达并不能保护细胞免受谷氨酸、多巴胺的侵害 或H2O2诱导的细胞凋亡。因此，tBHQ 提供的保护不应 简单地说是 QR 的增加，但通过协调调节多个基因 一个共同的机制。我们的实验室表明，tBHQ 通过以下方式提高 QR： 人神经母细胞瘤中抗氧化反应元件（ARE）的激活 细胞和原代神经胶质细胞培养物。我们假设表达增加 ARE 驱动的基因可阻止氧化应激诱导的细胞死亡。具体的 该提案的目的是： 1）确定分子机制 tBHQ 激活人神经母细胞瘤细胞中的 ARE 并增加 QR； 2） 表征 ARE 体内表达模式和调控； 3） 确定淀粉样前体蛋白过度表达对 QR 和 阿尔茨海默病转基因小鼠模型中的 ARE； 4）表征 对照组和 AD 患者人脑中 QR 的表达模式。 氧化应激增加与神经元细胞死亡有关 急性损伤，如癫痫、缺血和低血糖。氧化应激是 也被认为是许多慢性病发展的主要因素 神经退行性疾病，例如阿尔茨海默氏症、帕金森氏症、亨廷顿舞蹈症和 肌萎缩侧索硬化症。氧化应激是一种不平衡，其中游离 自由基及其产物超出抗氧化防御能力 机制。产物形成的增加和/或保护机制的损失 可以扰乱这种平衡。目前，我们对如何或通过什么方式知之甚少 神经退行性疾病，例如阿尔茨海默病（具体目标 3 和 4）。 阐明大脑中调节 ARE 基因的分子机制， 因此，对于开发缓解或缓解的治疗方法可能至关重要 预防，神经毒性。