CYOTSKELETAL OXIDATIVE MODIFICATIONS

描述（改编自申请人的摘要）：阿尔茨海默病（AD）和 帕金森病（PD）是使人衰弱的神经退行性疾病， 其特征在于蛋白质聚集体的沉积。这些聚集体 与氧化应激标志物的存在相关，这表明 聚集体的形成或它们的毒性是由 氧化应激根据免疫细胞化学和 生化研究在前一个赠款期间，研究人员假设， 氧化损伤是自催化的：最初产生的活性氧 活性氧（ROS），产生脂氧化和糖氧化产物。内收 至少两种这样的突出的反应性醛，4-羟基壬烯醛（HNE），和 乙二醛，已被观察到创造新的结合位点的外来铁和 Cu离子，以结合的金属能够催化还原的方式 O2或H2 O2，产生额外的ROS。这种氧化还原循环产生 ROS的稳定通量进一步氧化聚集体的成分， 以及附近的脂质和糖，从而放大了最初的氧化损伤。 所提出的假设的新颖之处在于认识到， 脂氧化和糖氧化修饰产物增强，或者直接增强， 或间接地，蛋白质聚集体通过 它们与外来氧化还原活性金属离子的结合。小心地 表征氧化损伤诱导的化学性质， 研究人员将研究金属离子的影响， 和对A-β的聚集和氧化的修饰， 螺旋状顺向-tau和α-突触核蛋白。将这些结果与 在其预制聚集体上产生的氧化损伤模式将 揭示聚集是否抑制或促进个别类型的氧化。 与此同时，研究人员将继续研究 免疫细胞化学研究显示， 大脑尸检材料具有确定特异性的抗体将促进 确定氧化应激的时空特征， 质谱研究将用于识别和量化化学物质 检测到的氧化损伤的性质。提案的独特优势 是免疫细胞化学研究和化学和 特定缺陷的质谱表征。结果应 提供诊断标志物，并帮助建立更好的理由， 药物干预。

DESCRIPTION (adapted from applicant's abstract): Alzheimer's Disease (AD) and Parkinson's Disease (PD) are debilitating neurodegenerative diseases that are characterized by the deposition of protein aggregates. These aggregates are correlated with the presence of oxidative stress markers, suggesting that either the formation of the aggregate or their toxicity is mediated by oxidative stress. Based on results obtained from immunocytochemical and biochemical studies in the previous grant period, the investigators hypothesize that oxidative insult is autocatalytic: Initially generated reactive oxygen species (ROS), generate lipoxidtaion and glycoxidation products. The adduction of at least two such prominent reactive aldehyde, 4-hydroxynonenal (HNE), and glyoxal, has been observed to create new binding sites for adventitious Fe and Cu ions, in a manner that the bound metals are capable of catalyzing reduction of either O2 or H2O2, generating additional ROS. This redox cycling generates a steady flux of ROS that further oxidizes the constituents of the aggregates as well as nearby lipids and sugars, thus amplifying the initial oxidative insult. The novel aspect of the proposed hypothesis is the recognition that lipoxidative and glycoxidative modification products enhance, either directly or indirectly, the ability of the protein aggregates to generate ROS through their binding of adventitious redox active metal ions. In order to carefully characterize the chemical nature of oxidative damage induced by adventitiously-bound metals, investigators will study the effect of metal ions and aldehydic modifies on the aggregation and oxidation of A-beta, paired helical filament-tau and alpha-synuclein. A comparison of these results to the patterns of oxidative damage generated on their preformed aggregates will reveal whether aggregation inhibits or promotes individual types of oxidation. In parallel the investigators will continue the studies of the chemical nature and time course of oxidative stress revealed by immunocytochemical studies of brain autopsy material. Antibodies of defined specificity will facilitate the identification of the spatio-temporal characteristics of oxidative stress while mass spectroscopic studies will be used to identify and quantify the chemical nature of the oxidative lesions detected. The unique strength of the proposal is the interplay between the immunocytochemical studies and the chemical and mass spectroscopic characterization of specific defects. The results should provide diagnostic markers and help establish an improved rationale for pharmaceutical intervention.