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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要衰老是一个复杂的过程，几乎影响生物体的所有重要参数，其特征是整体许多细胞功能下降，导致疾病和死亡风险增加。作为所占比例全球人口老龄化持续增长，与年龄相关的疾病的发生率也随之增加，对大脑老化影响最具破坏性的是痴呆症和阿尔茨海默病。因此，有一个迫切需要发现新的治疗方法来改善老年人的健康。多年来，基因表达模式的改变已被证明与人类衰老经历相关，但是是什么推动了这种变化尚不清楚。新的证据表明染色质的表观遗传变化级别负有主要责任；然而，它们在衰老过程中的确切作用尚未得到测试，因为缺乏实验模型。为了直接测试衰老过程中表观遗传变化的因果关系，我们已经生成了一种新的小鼠模型，称为 ICE 小鼠，用于表观基因组的诱导变化，这将使我能够通过在以下位置诱导非诱变、位点特异性核 DNA 断裂来引发表观遗传变化：使用他莫昔芬的一些基因组位点。因为 ICE 系统可以实现准确的时间和空间控制表观遗传变化，我将能够测试染色质水平的修饰是否是导致或专门影响大脑的疾病的影响，例如认知能力下降和阿尔茨海默病。迄今为止的结果支持这样的假设：表观基因组的改变可以引发衰老加速哺乳动物。该项目旨在开发神经元特异性 ICE 小鼠，以阐明其潜在机制驱动年龄相关认知障碍的机制（目标 1），使用 ICE 系统来确定表观遗传是否变化可以驱动阿尔茨海默病的发作和进展（目标 2），并研究染色质如何修饰会在痴呆和神经退行性疾病期间特异性破坏线粒体（目标 3）。采取总之，这个项目将为衰老过程的根本机制提供新的有价值的见解，关注大脑衰老疾病，揭示潜在的生物标志物，并强调改善的治疗策略人类状况。所有三个目标的部分内容将在 K99 培训阶段开始，并在表观遗传学和衰老领域的专家 David Sinclair 博士和脑衰老和衰老领域的领导者 Li-Huei Tsai 博士阿尔茨海默病，这项工作是在哈佛医学院进行的，该学院是一所杰出的学术和研究机构研究机构。所有三个目标的各个方面都将在 R00 独立阶段继续进行。该资金将让我能够将我的研究扩展到新的技术、知识和新的方向概念，研究神经科学、衰老、疾病和线粒体生物学的交叉点。这样，我就会能够发展自己的研究领域，在组建自己的研究小组时我将对其进行扩展。