ALUMINUM INDUCED INTERACTIONS AND NEUROLOGICAL DISEASE

铝引起的相互作用和神经系统疾病

• 批准号: 2909993
• 负责人: STEPHEN C BONDY
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2909993
• 关键词: Alzheimer's disease; Mammalia; acetylcholine; aging; aluminum; amyloid proteins; antioxidants; chelating agents; clone cells; free radicals; human tissue; immunocytochemistry; intermolecular interaction; iron; metal metabolism; metal poisoning; molecular pathology; nervous system disorder; neurotoxicology; oxidative stress; postmortem; stress proteins; synaptosomes; transferrin; vitamin therapy

DESCRIPTION: (Applicant's Abstract) Aluminum has been long suspected to play a role in several neurological diseases associated with aging, but this linkage has never been unequivocally established. There is evidence that the potential of iron for enhancing free radical generation in nervous tissue is enhanced by aluminum, although this latter metal has no intrinsic pro-oxidant properties. The intent of this application is to illuminate the underlying molecular mechanisms by which such a potentiation may take place. The effect of chelation or protein sequestration of either metal upon their interactions will be examined. The biological substrate responsive to such oxidative stress induced by the combined metals, will be sought. The nature of the induced reactive oxygen species will be documented using both enzymic and electron spin resonance techniques. Subsequently, the biological relevance of aluminum-iron interactions will be investigated in animals exposed to these metals singly or in combination. The concentrations of these metals in various brain regions will be quantitated by atomic absorption. An attempt to correlate levels of aluminum and oxidative parameters in human post-mortem cerebral tissue from aged and Alzheimer's brains will also be made. In addition to study of parameters relating to oxidative damage to proteins, and membrane stability in dosed animals, and in treated cholinergic neuroblastoma cells, key proteins such as ubiquitin, beta-amyloid, and heat shock protein HSP 70, will be quantitated by immunological procedures. The final phase of the planned research is an attempted mitigation of changes induced in neural tissue in vitro and in vivo by these combined metals. This will involve dietary supplementation with antioxidant vitamins or the use of selective chelators. Results will illuminate the role that aluminum may play in potentiation of age-related neurological diseases.

描述：（申请人的摘要）长期怀疑铝 在与衰老有关的几种神经系统疾病中发挥作用， 但是这种联系从未明确建立。有 证据表明铁的潜力增强了自由基 铝在神经组织中产生的产生，尽管这是 后一种金属没有固有的促氧化特性。意图 该应用是阐明基本的分子机制 可以进行这种增强性。螯合的影响或 两种金属在相互作用时的蛋白质固换将是 检查。对这种氧化应激有反应的生物底物 由合并金属诱导，将寻求。的本质 诱导的活性氧将使用酶和 电子自旋共振技术。随后，生物学 铝铁相互作用的相关性将在动物中研究 单独或结合使用这些金属。浓度 这些金属中的各个大脑区域将通过原子定量 吸收。 试图将铝和氧化参数的水平相关联 来自老年和阿尔茨海默氏症大脑的验尸后脑组织 也可以做。除了研究与氧化有关的参数 蛋白质的损害和剂量动物的膜稳定性，以及 处理过的胆碱能神经母细胞瘤细胞，关键蛋白，例如泛素， β-淀粉样蛋白和热激蛋白HSP 70将通过 免疫程序。计划研究的最后阶段是 试图缓解体外神经组织引起的变化的尝试 这些合并金属的体内。这将涉及饮食 补充抗氧化剂维生素或使用选择性 螯合剂。结果将阐明铝可能扮演的角色 与年龄有关的神经疾病的增强。