Gene Regulation and DNA Damage in the Aging Brain

衰老大脑中的基因调控和 DNA 损伤

• 批准号: 7124202
• 负责人: Bruce A YANKNER
• 金额: $ 33.93万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124202
• 关键词: DNA damage; DNA repair; aging; apoptosis; behavior test; brain; centenarian human (100+); chromatin immunoprecipitation; gene expression; gene expression profiling; gene induction /repression; genetic promoter element; genetic regulation; genetically modified animals; human tissue; laboratory mouse; longevity; microarray technology; mitochondrial DNA; molecular biology information system; neural plasticity; neuropathology; neuroprotectants; polymerase chain reaction; postmortem; western blottings

DESCRIPTION (provided by applicant): 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 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 transcriptional co-repressor NCOR1, the human ortholog of the yeast longevity gene SIR2 (Sirt1), and the DNA repair enzyme hOGG1. Moreover, centenarian cases of extreme longevity show increased expression of DNA repair and anti-apoptotic genes in the brain. 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 neurodegenerative diseases. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in the normal aging human brain and in centenarians. 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 will be defined. In addition, the role of neuroprotective DNA repair and anti-apoptotic signaling pathways will be explored in individuals with extreme longevity. Transgenic mice that overexpress nuclear and mitochondrial DNA repair enzymes will be generated to determine whether DNA damage contributes to age-related cognitive decline. 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一个原因，也是阿尔茨海默病和帕金森病的主要危险因素。最近一项令人兴奋的进展是阐明了衰老人脑中 DNA 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，我们已经开始定义受损基因沉默的机制，方法是获得核蛋白复合物参与的证据，该复合物包含转录共阻遏物 NCOR1、酵母长寿基因 SIR2 (Sirt1) 的人类直系同源物和DNA修复酶hOGG1。此外，极端长寿的百岁老人的大脑中 DNA 修复和抗凋亡基因的表达增加。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易感性的基础。该提案中的研究将建立一个全基因组数据库，记录正常衰老人脑和百岁老人的基因表达和 DNA 损伤。我们将研究衰老大脑中选择性 DNA 损伤和基因沉默的机制，并确定新定义的 DNA 损伤沉默复合物的作用。此外，还将探索极长寿个体中神经保护性 DNA 修复和抗凋亡信号通路的作用。将产生过度表达核和线粒体 DNA 修复酶的转基因小鼠，以确定 DNA 损伤是否会导致与年龄相关的认知能力下降。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。