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Mechanisms underlying DNA double strand break response in Alzheimer?s disease and frontal temporal dementia

阿尔茨海默病和额颞叶痴呆中 DNA 双链断裂反应的机制

基本信息

批准号：
10210448
负责人：
Li-Huei Tsai
金额：
$ 40.14万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2017-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210448
关键词：
APP-PS1 Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloidosis Antibodies Biological Assay Brain Cells ChIP-seq Cognition Comet Assay DNA Damage DNA Double Strand Break DNA Repair DNA lesion DNA-Binding Proteins Deacetylase Defect Deterioration Development Disease Double Strand Break Repair Emerging Technologies Event Failure Frontotemporal Dementia Gamma-H2AX Genome Genome Stability Genomic DNA Genomic Instability Goals HDAC1 gene Histones Human Impaired cognition Knowledge Link Lysine Maps Measurement Measures Mediating Methods Modeling Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nucleosomes Pathologic Patients Pharmacology Phosphorylation Physiological Predisposition Process RNA Research SIRT1 gene Signal Transduction Site Source System Tauopathies Technology Testing Therapeutic Intervention Variant Work base brain health cognitive function familial Alzheimer disease familial amyotrophic lateral sclerosis frontotemporal lobar dementia-amyotrophic lateral sclerosis gene product genome-wide genomic locus high throughput screening human model improved induced pluripotent stem cell insight mouse model neuronal survival neurotoxic new therapeutic target novel recruit repaired response screening small molecule stem cell model targeted treatment

项目摘要

DNA damage perturbs genomic stability and has been linked to age-associated cognitive decline, as well as to early stages of various neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and frontotemporal dementia (FTD). However, our mechanistic understanding of how DNA damage contributes to neuronal vulnerability and deterioration remains an unresolved, yet extremely important question. A major confounding factor is that the sources of damage that are most pertinent to neurodegeneration remain unknown and the precise mechanisms that connect genomic instability to neurodegeneration are poorly understood. In addition, it is unclear whether the deterioration of brain function results solely from a random accumulation of DNA damage throughout the genome, or whether there are “hotspots” of damage that mediate this process. The goal of our research is to better understand the mechanisms underlying genomic instability in neurodegeneration and identify novel therapeutic targets to dampen this early pathological hallmark of neuronal vulnerability. We hypothesize that genomic instability is a major underlying mechanism of cognitive decline and neuronal vulnerability in AD and FTD. Towards testing this hypothesis, our specific aims are: 1) to identify genomic loci that are vulnerable to the accumulation of DNA damage, particularly DNA double strand breaks (DSBs) in mouse and human induced pluripotent cell (iPSC)-derived models of AD and FTD, 2) to determine the precise defects in DSB signaling/repair in mouse and human iPSC-derived models of AD and FTD, and 3) to identify modifiers that reduce DNA damage susceptibility in iPSC-derived neural cells from patients with familial AD and FTD using a novel high-throughput screening strategy. Our preliminary findings suggest that excessive DNA DSBs are an early pathological hallmark of neurodegeneration that can be modeled in both mouse and human systems. Obtaining increased mechanistic insight into the failure to respond to and/or repair DNA DSBs in the context of neurodegenerative mutations will broaden our understanding of how genomic instability contributes to decline in brain health and cognition, and provide novel avenues for early therapeutic intervention in neurodegeneration.

DNA 损伤会扰乱基因组稳定性，并与年龄相关的认知能力下降以及各种神经退行性疾病的早期阶段，包括阿尔茨海默病 (AD)、肌萎缩侧索硬化症硬化症和额颞叶痴呆（FTD）。然而，我们对 DNA 损伤机制的理解导致神经元脆弱性和恶化的问题仍未解决，但极其重要问题。一个主要的混杂因素是与最相关的损害来源神经退行性变仍然未知，并且将基因组不稳定与神经退行性变联系起来的确切机制人们对神经退行性疾病知之甚少。此外，尚不清楚大脑功能是否会恶化完全是由于整个基因组中 DNA 损伤随机积累的结果，或者是否存在调解这一过程的损害“热点”。我们研究的目标是更好地了解神经退行性变中基因组不稳定的机制，并确定新的治疗靶点抑制神经元脆弱性的这种早期病理特征。我们假设基因组不稳定性是 AD 和 FTD 认知能力下降和神经元脆弱性的主要潜在机制。走向测试根据这一假设，我们的具体目标是：1）确定易受累积影响的基因组位点 DNA 损伤，特别是小鼠和人类诱导多能细胞中的 DNA 双链断裂 (DSB) (iPSC) 衍生的 AD 和 FTD 模型，2) 确定小鼠 DSB 信号传导/修复的精确缺陷以及人类 iPSC 衍生的 AD 和 FTD 模型，以及 3) 识别减少 DNA 损伤的修饰剂使用新型高通量方法研究家族性 AD 和 FTD 患者 iPSC 衍生神经细胞的易感性筛选策略。我们的初步研究结果表明，过量的 DNA DSB 是一种早期病理现象。神经退行性变的标志，可以在小鼠和人类系统中建模。获得增加对神经退行性疾病背景下未能响应和/或修复 DNA DSB 的机制洞察突变将加深我们对基因组不稳定性如何导致大脑健康下降的理解认知，并为神经退行性疾病的早期治疗干预提供新途径。