COBRE: UND: CARBONYL DETOXIFICATION IN CNS

COBRE：UND：中枢神经系统中的羰基解毒

• 批准号: 7381901
• 负责人: MATTHEW J PICKLO
• 金额: $ 18.36万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381901
• 关键词: COBRE; UND; CARBONYL; DETOXIFICATION; CNS

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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。阿尔茨海默病（AD）和其他毁灭性的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。特别是，对脂质的氧化损伤会产生大量的细胞毒性羰基。我们假设羰基如4-羟基壬烯醛（HNE）的解毒作用是神经退行性疾病发病机制的一个因素，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的中得到验证：(1)确定HNE在中枢神经系统组织中的代谢。这将包括分析大鼠脑切片中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会改变细胞毒性损伤的效力。这将涉及稳定的、转基因的人类神经细胞系和成年大鼠星形胶质细胞的原代培养的生产，(3)确定羰基解毒是否可以在药理学上提高中枢神经系统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为中枢神经系统解毒有害羰基的途径提供新的理解。这些数据可能导致形成新的预防和治疗策略的神经退行性疾病。