DNA DAMAGE AND NEURODEGENERATION IN THE AGING BRAIN

衰老大脑中的 DNA 损伤和神经退行性变

• 批准号: 7085089
• 负责人: Bruce A YANKNER
• 金额: $ 34.78万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085089
• 关键词: Alzheimer' s disease; DNA damage; DNA repair; N glycosidase; aging; amidohydrolases; amyloid proteins; apoptosis; behavior test; cognition disorders; enzyme activity; gene expression; gene induction /repression; genetically modified animals; human tissue; laboratory mouse; memory; neural degeneration; neurogenetics; oxidative stress; postmortem; space perception

The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's and Parkinson's disease. An exciting recent development is the elucidation of a pattern of DNA damage in the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity, vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be explained, at least in part, by oxidative DMA damage to vulnerable gene promoters provides a novel conceptual framework for understanding how the brain ages. Furthermore, we have begun to define the mechanism by which damaged genes are silenced by obtaining evidence for the involvement of a nuclear protein complex that contains the transcriptional co-repressor NCOR1, the human ortholog of the yeast ongevity gene SIR2 (Sirt1), and the DNA repair enzyme hOGG1. Our preliminary studies also suggest that this age-related process may be accelerated in Alzheimer's disease, and may predispose to aggregation of amyloid beta-protein (Abeta). These findings provide the basis for our hypothesis that DNA damage contributes to reduced expression of important neuronal genes in the aging brain, and that this process may underlie cognitive decline and vulnerability to neurodegeneration. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in the normal aging human brain. The mechanisms of selective DNA damage and gene silencing in the aging brain will be investigated, and the role of the newly defined DNA damage silencing complex involving Sirt1 (Project 3) will be defined. Transgenic mice that oyerexpress DNA repair enzymes will be generated to determine whether DNA damage contributes to age-related cognitive decline. These mice will also be mated with APPsw and Ck-p25 transgenic mice generated in Project 2 to determine the role of age-related DNA damage in the pathology of Alzheimer's disease. These studies may provide new insights into brain aging, with potentially significant therapeutic implications.

大脑老化是老年人认知能力下降的一个原因，也是老年痴呆症的主要危险因素 和帕金森氏症一个令人兴奋的最新进展是阐明了一种DNA损伤模式， 衰老的人脑与介导突触可塑性的基因表达减少有关， 囊泡运输和线粒体功能。我们发现了大脑衰老的“基因特征”， 至少部分地解释了氧化DMA损伤脆弱的基因启动子提供了一种新的 理解大脑如何衰老的概念框架。此外，我们已经开始定义 通过获得参与细胞核的证据来沉默受损基因的机制 一种蛋白质复合物，含有转录辅助抑制因子NCOR 1，即酵母的人类直系同源物 长寿基因SIR 2（Sirt 1）和DNA修复酶hOGG 1。我们的初步研究还表明， 这种与年龄相关的过程可能在阿尔茨海默病中加速，并且可能倾向于聚集 淀粉样β蛋白（Abeta）。这些发现为我们的假设提供了基础，即DNA损伤有助于 衰老大脑中重要神经元基因的表达减少，这一过程可能是 认知能力下降和易受神经退化的影响。本提案中的研究将建立一个 正常老化人脑中基因表达和DNA损伤的全基因组数据库。的 将研究衰老大脑中选择性DNA损伤和基因沉默的机制， 新定义的涉及Sirt 1的DNA损伤沉默复合物（项目3）的作用将被定义。 将产生表达DNA修复酶的转基因小鼠，以确定DNA是否 损伤会导致与年龄相关的认知能力下降。这些小鼠也将与APPsw和Ck-p25交配 在项目2中产生的转基因小鼠，以确定年龄相关的DNA损伤在病理学中的作用， 老年痴呆症这些研究可能为大脑衰老提供新的见解， 治疗意义