COBRE: UND: CARBONYL DETOXIFICATION IN CNS

COBRE：UND：中枢神经系统中的羰基解毒

• 批准号: 7610477
• 负责人: MATTHEW J PICKLO
• 金额: $ 18.95万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-07 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610477
• 关键词: 4 hydroxynonenal; Adult; Aldehyde dehydrogenase (NAD+); Alzheimer' s Disease; Astrocytes; Biochemical; Brain; Cell Line; Chronic; Class; Computer Retrieval of Information on Scientific Projects Database; DNA; Data; Disease; Drug Metabolic Detoxication; Elderly; Elevation; Environmental Risk Factor; Enzymes; Funding; Genetic; Grant; Human; In Vitro; Institution; Lead; Lipids; Measures; Metabolic; Metabolism; Mitochondria; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Production; Proteins; Rattus; Research; Research Personnel; Resources; Screening procedure; Slice; Source; Testing; Therapeutic; Tissues; Transgenic Organisms; United States National Institutes of Health; aldehyde dehydrogenases; cytotoxic; in vivo; mitochondrial dysfunction

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 阿尔茨海默氏病（AD）和其他毁灭性慢性神经退行性疾病（例如帕金森氏病（PD））涉及多种因素，例如增长年龄，遗传背景和环境因素。在生化水平上，这些疾病的标志是对DNA，脂质和蛋白质以及线粒体功能障碍的氧化损伤升高。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许多细胞毒性羰基。我们假设羰基的排毒（如4-羟基诺烯纳尔（HNE））是神经退行性疾病发病机理的一个因素，并且羰基代谢的改变改变了细胞毒性损伤的效力。这些假设将在以下特定目的中进行检验：（1）确定中枢神经系统组织中HNE的代谢。这将涉及分析大鼠脑切片中HNE的代谢命运以及人脑中HNE代谢产物的内源水平，（2）定义线粒体，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，神经元细胞系和成年大鼠星形胶质细胞的原发性培养物，（3）确定在中枢神经系统中是否可以将羰基排毒作为一种潜在的治疗措施，在中枢神经系统中升高。这将涉及单功能诱导剂的体外和体内筛选。从成功完成这些特定目标中收集的数据将提供对中枢神经系统对有害羰基排毒的途径的新理解。这些数据可能导致形成神经退行性疾病的新预防和治疗策略。