DNA DAMAGE AND NEURODEGENERATION IN THE AGING BRAIN

大脑老化是老年人认知能力下降的原因之一，也是阿尔茨海默氏症的主要危险因素 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 与调节突触可塑性的基因表达减少有关的老化的人脑， 囊泡运输和线粒体功能。我们发现大脑老化的“基因特征”可能是 至少部分解释了由氧化损伤的DMA对脆弱基因启动子的破坏提供了一种新的 了解大脑如何衰老的概念框架。此外，我们已经开始定义 通过获得核参与的证据而使受损基因沉默的机制 含有转录共抑制因子NCOR1的蛋白质复合体，NCOR1是酵母的人类同源物 长寿基因Sirt1和DNA修复酶hOGG1。我们的初步研究也表明 这种与年龄相关的过程在阿尔茨海默病中可能会加速，并可能易于聚集 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基因的表达减少，这一过程可能是 认知能力下降和易患神经退行性变。这项建议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。这个 我们将研究衰老大脑中选择性DNA损伤和基因沉默的机制，以及 将确定新定义的涉及Sirt1的DNA损伤沉默复合体(项目3)的作用。 将产生表达DNA修复酶的转基因小鼠，以确定DNA 损伤会导致与年龄相关的认知能力下降。这些小鼠还将与appsw和ck-p25交配。 项目2中产生的转基因小鼠，以确定年龄相关DNA损伤在糖尿病病理中的作用 阿尔茨海默氏症。这些研究可能为大脑老化提供新的见解，具有潜在的重大意义 治疗方面的影响。

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.