ALUMINUM/IRON INTERACTIONS IN NEURODEGENERATIVE DISEASE

描述：(逐字摘自申请者的摘要)铝长期以来一直是 被怀疑与几种神经疾病有关 老龄化，但这种联系从未明确地建立起来。相对的 铝盐的惰性被认为否定了这种可能性。 矛盾的是，调查人员最近的发现表明，这非常 惰性可能会引发神经毒性反应。此外，尽管铝已经 没有内在的促氧化剂特性，它们有证据表明潜在的 促进神经组织自由基生成的过渡金属是 采用铝材增强。这些发现为下面的研究奠定了基础 研究目标：(1)确定精确的化学和分子基础 铝对过渡金属诱导的自由基的增强作用 神经组织内的活动。铝对Fenton化学和化学结构的影响 我们将考察几种过渡金属的氧化状态。(2)定位 铝影响组织的解剖区域和细胞类型 损坏。(3)确定细胞内信号级联的顺序 动物和人(神经细胞和神经胶质细胞)细胞系对 铝暴露。第二信使通路及其相应的变化 转录因子将被记录在案。泛素等关键蛋白质， 细胞因子、热休克蛋白70、锌指蛋白和NFkB将通过 免疫学或凝胶移位程序。无论铝的性质 胶体可以是内在有毒的，或者β-淀粉样蛋白的毒性是否可以 将得到增强，这将被确定。(4)追踪延伸铝的影响 暴露于神经组织内的基因组表达。这将包括化验 线粒体DNA的缺失。(5)探索可能的药理作用 干预措施可防止暴露于 铝制的。这将涉及饮食或生长介质的补充， 抗氧化剂或选择性螯合剂的使用。加在一起，这五个人 目标勾勒出一种研究战略，将允许解决 铝与神经系统相关的似乎相互矛盾的证据 退化。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Aluminum has long been suspected to play a role in several neurological diseases associated with aging, but this linkage has never been unequivocally established. The relative inertness of aluminum salts has been cited as negating this possibility. Paradoxically, the investigator's recent findings suggest that this very inertness may provoke a neurotoxic response. In addition, although aluminum has no intrinsic pro-oxidant properties, they have evidence that the potential of transition metals for enhancing free radical generation in nervous tissue is enhanced by aluminum. These findings serve as the foundation for the following research objectives: (1) To define the precise chemical and molecular basis underlying aluminum's potentiation of transition-metal induced free radical activity within nervous tissue. The effect of aluminum on Fenton chemistry and oxidation state of several transition metals will be examined. (2) To locate the anatomical regions and cell types in which aluminum can effect tissue damage. (3) To define the sequence of the intracellular signaling cascades in doses animals and in human (neuronal and glial) cell lines responding to aluminum exposure. Second messenger pathways and consequent changes in transcription factors will be documented. Key proteins such as ubiquitin, cytokines, HSP 70, zinc finger proteins and NFkB will be quantified by immunological or gel shift procedures. Whether the properties of aluminum colloid can be intrinsically toxic or whether the toxicity of beta-amyloid can be enhanced will be determined. (4) To tract the effects of extended aluminum exposure upon genomic expression within neural tissues. This will include assay for deletions in mitochondrial DNA. (5) To explore possible pharmacological interventions that may prevent changes within neural tissues exposed to aluminum. This will involve dietary or growth media supplementation with antioxidant agents or the use of selective chelators. Together, these five objectives delineate a research strategy that will allow resolution of the seemingly contradictory evidence relating aluminum to neurological degeneration.