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: 7907457
• 负责人: Bruce A YANKNER
• 金额: $ 9.99万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907457
• 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（由申请人提供）：大脑的衰老是老年人认知能力下降的原因，是神经退行性疾病的主要危险因素。令人兴奋的最新发展是阐明了衰老的人脑中DMA损伤模式，这与介导突触可塑性，囊泡转运和线粒体功能的基因表达降低有关。我们发现，至少部分通过氧化DNA对弱势基因启动子损害的脑老化的“遗传特征”可以解释，这为了解大脑的年龄提供了一种新颖的概念框架。此外，我们已经开始定义通过获得含有寿命基因SIRTL，转录共抑制NCOR1和DNA修复酶Hogg1的核蛋白质复合物的证据来定义受损基因被损坏的基因沉默的机制。我们的初步研究还提高了与年龄相关的.DNA损伤和基因沉默可能倾向于阿尔茨海默氏病的病理。 CDK5失调的CK-P25转基因小鼠模型的发展进一步支持了这一假设，该模型显示出明显增加的DNA损伤和阿尔茨海默氏病病理学的特征。这些发现为我们的假设提供了基础，即DNA损伤有助于降低衰老大脑中重要的神经元基因的表达，并且该过程可能是认知能力下降和对神经变性的脆弱性的基础。该提案中的研究将在正常衰老的人大脑中建立一个全基因组的基因表达和DNA损伤数据，并将研究新定义的DNA损伤沉默复合物的作用，涉及寿命基因SIRT 1.转基因小鼠过表达DNA修复酶，并确定Apps and apps and ck-p2 trange dna损坏的型号，以确定：apps and ck-p2 trangiations tragitiations apps and ck-p2 5衰老的下降和阿尔茨海默氏病的病理。此外，将研究自噬作为在衰老大脑中氧化DNA损伤和蛋白质聚集的机制受损的作用。最后，将在正常衰老小鼠和人类神经退行性疾病的小鼠模型中测试一组新型的潜在治疗性SIRTL激活化合物。这些研究可能会对大脑衰老提供新的见解，并具有潜在的重要治疗意义。