DNA Damage and Neurodegeneration in the Aging Brain

衰老大脑中的 DNA 损伤和神经变性

• 批准号: 7907351
• 负责人: Bruce A YANKNER
• 金额: $ 24.81万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907351
• 关键词: DNA; Damage; Neurodegeneration; Aging; Brain

DESCRIPTION (provided by applicant): The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for neurodegenerative diseases. An exciting recent development is the elucidation of a pattern of DMA 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 DNA 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 longevity gene Sirtl, the transcriptional co-repressor NCOR1, and the DNA repair enzyme hOGG1. Our preliminary studies also raise the possibility that age-related .DNA damage and gene silencing may predispose to the pathology of Alzheimer's disease. This hypothesis is further supported by the development of the Ck-p25 transgenic mouse model of Cdk5 dysregulation that shows markedly increased DNA damage and features of the pathology of Alzheimer's disease. 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, and will investigate the role of a newly defined DNA damage silencing complex involving the longevity gene Sirt 1. Transgenic mice that overexpress DNA repair enzymes will be generated and mated with: APPsw and Ck-p25 transgenic mouse models to determine the role of age-related DNA damage in the cognitive decline of aging and the pathology of Alzheimer's disease. Moreover, the role of impaired autophagy as a mechanism of oxidative DNA damage and protein aggregation in the aging brain will be investigated. Finally, a novel set of potentially therapeutic Sirtl-activating compounds will be tested in normal aging mice and in mouse models of human neurodegenerative diseases. These studies may provide new insights into brain aging, with potentially significant therapeutic implications.

描述（申请人提供）：大脑老化是老年人认知能力下降的原因，也是神经退行性疾病的主要危险因素。最近一项令人兴奋的进展是阐明了衰老人脑中 DMA 损伤的模式，该模式与介导突触可塑性、囊泡运输和线粒体功能的基因表达减少有关。我们发现大脑衰老的“遗传特征”至少可以部分地通过对脆弱基因启动子的氧化DNA损伤来解释，这为理解大脑如何衰老提供了一个新的概念框架。此外，我们已经开始通过获得包含长寿基因 Sirtl、转录共阻遏物 NCOR1 和 DNA 修复酶 hOGG1 的核蛋白复合物参与的证据来定义受损基因沉默的机制。我们的初步研究还提出了与年龄相关的 DNA 损伤和基因沉默可能诱发阿尔茨海默氏病病理的可能性。 Cdk5 失调的 Ck-p25 转基因小鼠模型的开发进一步支持了这一假设，该模型显示 DNA 损伤显着增加，并具有阿尔茨海默病的病理学特征。这些发现为我们的假设提供了基础，即 DNA 损伤导致衰老大脑中重要神经元基因的表达减少，并且这一过程可能是认知能力下降和神经退行性疾病脆弱性的基础。该提案中的研究将建立正常衰老人脑中基因表达和 DNA 损伤的全基因组数据库，并将研究涉及长寿基因 Sirt 1 的新定义的 DNA 损伤沉默复合物的作用。过度表达 DNA 的转基因小鼠将生成修复酶并与 APPsw 和 Ck-p25 转基因小鼠模型交配，以确定与年龄相关的 DNA 损伤在衰老认知衰退和阿尔茨海默病病理学中的作用。此外，还将研究受损的自噬作为衰老大脑中 DNA 氧化损伤和蛋白质聚集机制的作用。最后，一组新的潜在治疗性 Sirtl 激活化合物将在正常衰老小鼠和人类神经退行性疾病小鼠模型中进行测试。这些研究可能为大脑衰老提供新的见解，并具有潜在的重大治疗意义。