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：（逐字研究申请人的摘要）人类染色体21 （HC21）据信与许多相关的武器基因 神经系统疾病，包括肌萎缩性侧硬化症（ALS 1）， 家族性阿尔茨海默氏病（FAD）和唐氏综合症（DS）。其中，DS 构成由部分或总三体构成的最常见疾病 HC21。 DS的特征是许多病理后果最多 重要的是导致早熟的老化通常伴随着 阿尔茨海默氏病（AD）。几个早期观察表明，一个小的HC21 段（唐氏综合症关键区域或DSCR），其中包含限制数字 遗传因素的大部分症状可能是造成大部分症状的原因。其他 HC21的区域，甚至是异源二倍体染色体上存在的一些基因 也可能通过补偿性促进DS的复杂表型 或加性相互作用。假定这对于基因尤其如此 哪种抗氧化酶的代码以及分散在整个过程中 核基因组。鉴于三体性的事实，这具有特别的意义 HC21的摄入导致至少两种酶的过表达 在活性氧（ROS）的生产和代谢中，即 超氧化物歧化酶（SOD I）和羰基还原酶（CBR）。在没有 位于异源的其他抗氧化基因的补偿性支持 染色体（例如谷胱甘肽过氧化物酶和过氧化氢酶基因），三体 HC21可能导致高度反应性羟基自由基的积累 可能严重损害细胞的功能完整性。一个重要 这种情况的结果将是线粒体DNA中的病变 特别容易受到氧化损伤的影响。现在的主要目标 项目是（a）检查一些关键基因之间的相互作用 trisomic CH21和其他染色体基因，以及（b）以验证抗氧化剂是否存在 例如辅酶Q，维生素E和抗坏血酸，单独或中 结合，可能在至少部分恢复中发挥积极作用 trisomic HC21细胞的正常功能。