DOWN SYNDROME, MITOCHONDRIAL DNA AND OXIDATIVE STRESS

唐氏综合症、线粒体 DNA 和氧化应激

• 批准号: 6796809
• 负责人: SANTOSH K SINHA
• 金额: $ 21.39万
• 依托单位: BRAIN INSIGHTS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-10 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796809
• 关键词: Downs syndrome; aging; antioxidants; bioenergetics; cell age; chromosome 21; chromosome translocation; cytogenetics; detoxification; diploidy; drug interactions; family genetics; free radical oxygen; gender difference; gene expression; gene interaction; human genetic material tag; mitochondrial DNA; northern blottings; oxidative stress; polymerase chain reaction; restriction fragment length polymorphism; superoxide dismutase; tissue /cell culture; trisomy

DESCRIPTION: (Verbatim from the Applicant's Abstract) Human chromosome 21 (HC21) harbors genes which is believed to be associated with a number of neurological diseases, including amyotrophic lateral sclerosis (ALS 1), familial Alzheimer disease (FAD), and Down syndrome (DS). Among these, DS constitutes the most common disease resulting from partial or total trisomy of HC21. DS is characterized by a number of pathological consequences the most important of which result in precocious aging often accompanied by signs of Alzheimer disease (AD). Several early observations indicated that a small HC21 segment (Down syndrome critical region or DSCR) containing a restricted number of genetic elements may be responsible for most of the Down symptoms. Other regions of HC21 and even some genes present on heterologous diploid chromosomes may also contribute to the complex phenotype of DS either through compensatory or additive interactions. This is presumed to be especially true for genes which code for antioxidant enzymes and which are dispersed throughout the nuclear genome. This has particular relevance in view of the fact that trisomy of HC21 leads to an overexpression of at least two enzymes which are implicated in the production and metabolism of reactive oxygen species (ROS), viz., superoxide dismutase (SOD I) and carbonyl reductase (CBR). In the absence of compensatory support from other antioxidant genes located on heterologous chromosomes (such as glutathione peroxidase and catalase genes), trisomy of HC21 may lead to an accumulation of highly reactive hydroxyl radicals which could severely damage the functional integrity of the cell. One important consequence of such a situation would be lesions in mitochondrial DNA that is especially vulnerable to oxidative injury. The major goals of the present project are to (A) examine the interactions between some of the the key genes of trisomic CH21 and other chromosomal genes, and (B) to verify if antioxidants such as coenzyme Q, vitamin E and ascorbic acid, individually or in combination, could play a positive role in at least partially restoring the normal functioning of trisomic HC21 cells.

描述：（逐字摘自申请人摘要）人类 21 号染色体 (HC21) 含有被认为与许多相关的基因 神经系统疾病，包括肌萎缩侧索硬化症 (ALS 1)、 家族性阿尔茨海默病（FAD）和唐氏综合症（DS）。其中，DS 是由部分或全部三体性引起的最常见疾病 HC21。 DS 最显着的特点是具有多种病理后果 其中重要的一点是导致性早熟，通常伴有以下症状： 阿尔茨海默病（AD）。一些早期观察表明，小型 HC21 包含有限数量的片段（唐氏综合症关键区域或 DSCR） 遗传因素可能是大多数唐氏症状的原因。其他 HC21 的区域，甚至异源二倍体染色体上存在的一些基因 也可能通过补偿性机制导致 DS 的复杂表型 或加性相互作用。这对于基因来说尤其如此 编码抗氧化酶并分散在整个身体中 核基因组。鉴于三体性这一事实，这具有特别的相关性 HC21 导致至少两种相关酶的过度表达 活性氧 (ROS) 的产生和代谢，即 超氧化物歧化酶（SOD I）和羰基还原酶（CBR）。在没有 来自位于异源的其他抗氧化基因的补偿支持 染色体（如谷胱甘肽过氧化物酶和过氧化氢酶基因）、三体性 HC21 可能会导致高反应性羟基自由基的积累，从而 可能会严重损害细胞的功能完整性。一个重要的 这种情况的后果将是线粒体DNA的损伤 特别容易受到氧化损伤。当前的主要目标 项目是（A）检查一些关键基因之间的相互作用 三体 CH21 和其他染色体基因，以及 (B) 验证抗氧化剂是否 例如辅酶 Q、维生素 E 和抗坏血酸，单独或组合在一起 的结合，可以在至少部分恢复方面发挥积极作用 三体 HC21 细胞的正常功能。