COBRE: UND: CARBONYL DETOXIFICATION IN CNS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。阿尔茨海默病(AD)和其他破坏性的慢性神经退行性疾病，如帕金森氏病(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，这些疾病的特点是DNA、脂质和蛋白质的氧化损伤增加，以及线粒体功能障碍。氧化损伤会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，4-羟基壬烯醛(HNE)等羰基化合物的解毒作用是神经退行性疾病发病机制中的一个因素，并且羰基代谢的改变改变了细胞毒性侮辱的效力。这些假说将在以下特定目标中得到验证：(1)确定HNE在中枢神经系统组织中的代谢。这将涉及分析HNE在大鼠脑片中的代谢命运和HNE代谢物在人脑中的内源性水平，(2)确定线粒体、2类和5类乙醛脱氢酶活性的调节是否会改变细胞毒性损伤的效力。这将涉及生产稳定的、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，(3)确定在中枢神经系统中是否可以通过药物作用提高羰基解毒作为一种潜在的治疗措施。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所收集的数据将提供对中枢神经系统解毒有害羰基的途径的新的理解。这些数据可能导致神经退行性疾病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.