The role of epigenetics in age-related cognitive decline and Alzheimer’s disease

表观遗传学在与年龄相关的认知能力下降和阿尔茨海默病中的作用

• 批准号: 9295606
• 负责人: Jaime Marie Ross
• 金额: $ 12.39万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295606
• 关键词: APP-PS1; Acceleration; Achievement; Address; Affect; Age-associated memory impairment; Aging; Aging-Related Process; Alopecia; Alzheimer' s Disease; Animal Model; Animals; Atrophic; Behavioral; Biological Assay; Biology; Brain; Brain region; Cell Culture Techniques; Cell Line; Cell Nucleus; Cell physiology; Cessation of life; Chromatin; Cicatrix; Cognition; Complex; DNA; DNA Packaging; Data; Defect; Dementia; Dependency; Development; Disease; Economic Burden; Encephalitis; Endonuclease I; Epigenetic Process; Etiology; Experimental Models; Funding; Gene Expression; Gene Expression Profile; Genomic approach; Genomics; Health; Heart; Histologic; Histology; Homeostasis; Homing; Human; Impaired cognition; Impairment; In Vitro; Incidence; Inflammation; Institution; Knowledge; Kyphosis deformity of spine; Language; Lead; Learning; Left; Life Expectancy; Link; Magnetic Resonance Spectroscopy; Mammals; Memory; Mentorship; Metabolic; Mitochondria; Modeling; Modification; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Nuclear; Organ; Organism; Osteoporosis; Pathology; Pathway interactions; Patients; Phase; Physarum polycephalum; Population; Process; Prosencephalon; Proteomics; Research; Role; Signal Pathway; Site; Stress; System; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Training; Transgenic Organisms; Translating; Work; age related; aging brain; aging population; base; chromatin modification; disability; disorder risk; epigenome; experience; human disease; improved; in vitro testing; in vivo; insight; medical schools; mitochondrial dysfunction; mouse model; normal aging; novel; potential biomarker; social; success; targeted treatment; therapeutic evaluation; virtual

PROJECT SUMMARY / ABSTRACT Aging is a complex process affecting virtually all vital parameters of an organism, characterized by an overall decrease in many cellular functions that lead to increasing risk of disease and death. As the proportion of the aging population continues to grow worldwide, so does the incidence of developing age-related disorders, with the most devastating affecting the aging brain, such as dementia and Alzheimer's disease. Thus, there is a tremendous need to discover novel treatments to increase the health of the aging populace. For years, alterations in gene expression patterns have been shown to correlate with the human aging experience, but what drives such changes is not known. Emerging evidence suggests that epigenetic changes at the chromatin level are largely responsible; however, their precise role in the aging process has been untested due to the lack of experimental models. In order to directly test the cause and effect of epigenetic changes during aging, we have generated a novel mouse model, denoted the ICE mouse for inducible changes in the epigenome, which will allow me to elicit epigenetic changes by inducing non-mutagenic, site-specific nuclear DNA breaks at a few genomic sites using tamoxifen. Because the ICE system allows for both accurate temporal and spatial control of the epigenetic changes, I will be able to test whether modifications at the chromatin level are cause or effect of disorders that specifically affect the brain, such as cognitive decline and Alzheimer's disease. Results to date support the hypothesis that alterations to the epigenome can trigger aging acceleration in mammals. This project aims to develop a neuronal-specific ICE mouse in order to illuminate the underlying mechanisms that drive age-related cognitive impairment (Aim 1), use the ICE system to determine if epigenetic changes can drive the onset and progression of Alzheimer's disease (Aim 2), and study how chromatin modifications specifically disrupt the mitochondria during dementia and neurodegeneration (Aim 3). Taken together, this project will provide new valuable insights into the underlying mechanisms of the aging process, focusing on brain aging disorders, reveal potential biomarkers, and highlight therapeutic strategies to improve the human condition. Portions of all three Aims will start during the K99 training phase, under the mentorship of Dr. David Sinclair, an expert in epigenetics and aging, and Dr. Li-Huei Tsai, a leader in brain aging and Alzheimer's disease, with the work taking place at Harvard Medical School, an exceptional academic and research institution. Aspects of all three Aims will continue during the R00 independent phase. The funds will allow me to expand my research into new directions with regards to new techniques, knowledge, and concepts, working at the interface of neuroscience, aging, disease, and mitochondrial biology. Thus, I will be able to develop my own research niche that I will expand upon when starting my own research group.

项目摘要 /摘要 衰老是一个复杂的过程，几乎影响了生物体的所有重要参数，其特征是 许多细胞功能的减少导致疾病和死亡的风险增加。作为比例 在全球范围内，人口衰老的人口继续增长，与年龄有关的疾病的发生率也随之增长。 影响大脑衰老的最毁灭性的，例如痴呆症和阿尔茨海默氏病。因此，有一个 巨大的需要发现新型治疗方法以增加衰老众人的健康状况。多年来， 基因表达模式的改变已显示与人类衰老经验相关，但 驱动这种变化的是未知的。新兴的证据表明表观遗传在染色质上的变化 水平在很大程度上负责；但是，由于 缺乏实验模型。为了直接测试衰老期间表观遗传变化的原因和影响 我们已经生成了一种新型的小鼠模型，表示冰小鼠的表观基因组可诱导的变化， 这将使我能够通过诱导非毒素特异性核DNA破裂来引起表观遗传变化。 使用他莫昔芬的一些基因组部位。因为冰系统允许准确的时间和空间 控制表观遗传变化，我将能够测试在染色质水平上的修饰是否是原因 或特别影响大脑的疾病的影响，例如认知能力下降和阿尔茨海默氏病。 迄今 哺乳动物。该项目旨在开发特定于神经元的冰鼠标，以照亮基础 驱动与年龄相关的认知障碍的机制（AIM 1），使用冰系统确定是否表观遗传 变化可以推动阿尔茨海默氏病的发作和进展（AIM 2），并研究染色质 修饰在痴呆和神经退行性过程中特异性破坏了线粒体（AIM 3）。拍摄 该项目将共同提供有关衰老过程的基本机制的新宝贵见解， 专注于大脑衰老疾病，揭示潜在的生物标志物，并强调改善治疗策略 人类状况。在K99训练阶段，这三个目标的一部分将在指导下开始 表观遗传学和衰老专家David Sinclair博士以及大脑衰老的领导者Li-Huei Tsai博士 阿尔茨海默氏病，这项工作是在哈佛医学院进行的，这是一所杰出的学术和 研究机构。在R00独立阶段，所有三个目标的各个方面都将继续。资金会 请让我将研究扩展到有关新技术，知识和知识方面的新方向 概念，在神经科学，衰老，疾病和线粒体生物学的界面上工作。因此，我会 能够开发自己的研究小众市场，在成立自己的研究小组时，我将扩展这些细分市场。