COBRE: UND: CARBONYL DETOXIFICATION IN CNS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。阿尔茨海默病（AD）和其他破坏性慢性神经退行性疾病如帕金森病（PD）涉及多种因素，如年龄增长、遗传背景和环境因素。在生化水平上，这些疾病的特征是DNA、脂质和蛋白质的氧化损伤升高以及线粒体功能障碍。氧化损伤导致有毒产物的形成。特别地，脂质的氧化损伤产生许多细胞毒性羰基。我们假设，羰基化合物如4-羟基壬烯醛（HNE）的解毒是神经退行性疾病发病机制中的一个因素，羰基代谢的改变改变了细胞毒性损伤的效力。这些假设将在以下具体目标中进行检验：（1）确定HNE在CNS组织中的代谢。这将涉及分析大鼠脑切片中HNE的代谢命运和人脑中HNE代谢物的内源性水平，（2）确定线粒体、2类和5类醛脱氢酶活性的调节是否改变细胞毒性损伤的效力。这将涉及生产稳定的转基因人类神经元细胞系和成年大鼠星形胶质细胞的原代培养物，（3）确定是否可以在CNS中提高羰基解毒作为潜在的治疗措施。这将涉及单功能酶诱导剂的体外和体内筛选。从这些特定目标的成功完成中收集的数据将提供对CNS解毒有害羰基化合物的途径的新理解。这些数据可能会导致神经退行性疾病的新的预防和治疗策略的形成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD) and other devastating chronic neurodegenerative disorders such as Parkinson's disease (PD) involve multiple factors such as advancing age, genetic background, and environmental factors. At the biochemical level these diseases are marked by elevations in oxidative damage to DNA, lipids, and proteins, and mitochondrial dysfunction. Oxidative damage leads to the formation of toxic products. In particular, oxidative damage to lipids generates numerous cytotoxic carbonyls. We hypothesize that the detoxification of carbonyls such as 4-hydroxynonenal (HNE) is a factor in the pathogenesis of neurodegenerative diseases and that alterations of carbonyl metabolism modifies the potency of cytotoxic insults. These hypotheses will be tested in the following specific aims: (1) determine the metabolism of HNE in CNS tissue. This will involve analyzing the metabolic fate of HNE in rat brain slices and endogenous levels of HNE metabolites in human brain, (2) define whether modulation of mitochondrial, class 2 and class 5 aldehyde dehydrogenase activity alters the potency of cytotoxic insults. This will involve the production of stable, transgenic human, neuronal cell lines and primary cultures of adult, rat astrocytes, (3) determine whether carbonyl detoxification can be pharmacologically elevated in the CNS as a potential therapeutic measure. This will involve the in vitro and in vivo screening of monofunctional enzyme inducers. The data gathered from the successful completion of these specific aims will provide new understanding of the pathways by which the CNS detoxifies harmful carbonyls. These data may lead to the formation of new preventative and therapeutic strategies for neurodegenerative disease.