CYOTSKELETAL OXIDATIVE MODIFICATIONS

描述(摘自申请者摘要)：阿尔茨海默病(AD)和 帕金森病(PD)是一种衰弱的神经退行性疾病， 以蛋白质聚集体沉积为特征的。这些聚集体是 与氧化应激标志物的存在相关，这表明 聚集体的形成或其毒性是由 氧化应激。基于免疫细胞化学和 在之前的资助期间，研究人员假设 这种氧化伤害是自动催化的：最初产生的活性氧 物种(ROS)，产生脂氧离子和糖氧化产物。引文 至少两种这种突出的反应性醛，4-羟基壬烯醛(HNE)，以及 乙二醛，已被观察到为不定态Fe和 铜离子，以结合金属能够催化还原的方式 O2或H2O2，产生额外的ROS。这种氧化还原循环产生一个 稳定的ROS通量，进一步将聚集体的组成氧化为 以及附近的脂肪和糖，从而放大了最初的氧化伤害。 提出的假设的新奇之处在于认识到 脂氧化性和糖氧化性修饰产物直接增强 或间接地，蛋白质聚集体通过产生ROS的能力 它们与外来氧化还原活性金属离子的结合。为了细心地 描述氧化损伤的化学性质 外星人结合的金属，研究人员将研究金属离子的影响 和醛修饰对A-β的聚集和氧化，配对 螺旋微丝-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 揭示聚集是抑制还是促进个别类型的氧化。 与此同时，调查人员将继续进行化学性质的研究。 免疫细胞化学研究揭示氧化应激的时间进程 脑部尸检材料。具有明确特异性的抗体将有助于 氧化应激的时空特征识别 将使用质谱学研究来鉴定和量化该化学物质 检测到的氧化损伤的性质。这项提议的独特优势 是免疫细胞化学研究和化学和 特定缺陷的质谱学表征。结果应该是 提供诊断标记物并帮助建立改进的理论基础 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.