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:
- 金额:$ 40.14万
- 依托单位:
- 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:
- 关键词:APP-PS1Age-associated memory impairmentAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidosisAntibodiesBiological AssayBrainCellsChIP-seqCognitionComet AssayDNA DamageDNA Double Strand BreakDNA RepairDNA lesionDNA-Binding ProteinsDeacetylaseDefectDeteriorationDevelopmentDiseaseDouble Strand Break RepairEmerging TechnologiesEventFailureFrontotemporal DementiaGamma-H2AXGenomeGenome StabilityGenomic DNAGenomic InstabilityGoalsHDAC1 geneHistonesHumanImpaired cognitionKnowledgeLinkLysineMapsMeasurementMeasuresMediatingMethodsModelingMusMutationNerve DegenerationNeurodegenerative DisordersNeuronsNucleosomesPathologicPatientsPharmacologyPhosphorylationPhysiologicalPredispositionProcessRNAResearchSIRT1 geneSignal TransductionSiteSourceSystemTauopathiesTechnologyTestingTherapeutic InterventionVariantWorkbasebrain healthcognitive functionfamilial Alzheimer diseasefamilial amyotrophic lateral sclerosisfrontotemporal lobar dementia-amyotrophic lateral sclerosisgene productgenome-widegenomic locushigh throughput screeninghuman modelimprovedinduced pluripotent stem cellinsightmouse modelneuronal survivalneurotoxicnew therapeutic targetnovelrecruitrepairedresponsescreeningsmall moleculestem cell modeltargeted 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损伤扰乱了基因组的稳定性,并与年龄相关的认知能力下降有关,
各种神经退行性疾病的早期阶段,包括阿尔茨海默氏病(AD)、肌萎缩侧索硬化症(ALS)和阿尔茨海默病(AD)。
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退化仍然是一个悬而未决的,但非常重要的
问题一个主要的混淆因素是,与以下方面最相关的损害来源
神经退行性变仍然是未知的,将基因组不稳定性与神经退行性变联系起来的确切机制仍然是未知的。
神经退行性变的研究知之甚少。此外,目前还不清楚大脑功能的恶化是否
仅仅是由于DNA损伤在整个基因组中的随机积累,或者是否有
“热点”的损害,调解这一进程。我们研究的目的是为了更好地了解
神经变性中基因组不稳定性的潜在机制,并确定新的治疗靶点,
抑制这种神经元脆弱性的早期病理标志。我们假设基因组的不稳定性是
AD和FTD中认知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)确定易受积累的基因组位点,
DNA损伤,特别是小鼠和人诱导多能细胞中的DNA双链断裂(DSB)
(iPSC)衍生的AD和FTD模型,2)确定小鼠中DSB信号传导/修复的精确缺陷
和人iPSC衍生的AD和FTD模型,以及3)鉴定减少DNA损伤的修饰剂
使用一种新的高通量方法在家族性AD和FTD患者的iPSC衍生神经细胞中的易感性
筛选策略我们的初步研究结果表明,过量的DNA双链断裂是一种早期病理性疾病,
这是一个神经退行性疾病的标志,可以在小鼠和人类系统中建模。争取更多的
在神经退行性疾病的背景下,对DNA DSB反应和/或修复失败的机制性见解
突变将拓宽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,并为神经变性的早期治疗干预提供新的途径。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Profiling DNA break sites and transcriptional changes in response to contextual fear learning.
- DOI:10.1371/journal.pone.0249691
- 发表时间:2021
- 期刊:
- 影响因子:3.7
- 作者:Stott RT;Kritsky O;Tsai LH
- 通讯作者:Tsai LH
Histone Deacetylases 1 and 2 in Memory Function.
- DOI:10.1021/acschemneuro.1c00775
- 发表时间:2022-03
- 期刊:
- 影响因子:5
- 作者:P. Pao;L. Tsai
- 通讯作者:P. Pao;L. Tsai
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Li-Huei Tsai其他文献
Li-Huei Tsai的其他文献
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{{ truncateString('Li-Huei Tsai', 18)}}的其他基金
Manipulating Neural Oscillations with Non-Invasive Sensory Stimulation for Alzheimer's Disease Intervention
通过非侵入性感觉刺激操纵神经振荡来干预阿尔茨海默病
- 批准号:
10378329 - 财政年份:2022
- 资助金额:
$ 40.14万 - 项目类别:
Manipulating Neural Oscillations with Non-Invasive Sensory Stimulation for Alzheimer's Disease Intervention
通过非侵入性感觉刺激操纵神经振荡来干预阿尔茨海默病
- 批准号:
10597073 - 财政年份:2022
- 资助金额:
$ 40.14万 - 项目类别:
Noninvasive sensory stimulation to promote glymphatic-lymphatic clearance for the treatment of Alzheimer’s Disease
无创感觉刺激促进类淋巴清除,治疗阿尔茨海默病
- 批准号:
10222930 - 财政年份:2021
- 资助金额:
$ 40.14万 - 项目类别:
Noninvasive sensory stimulation to promote glymphatic-lymphatic clearance for the treatment of Alzheimer’s Disease
无创感觉刺激促进类淋巴清除,治疗阿尔茨海默病
- 批准号:
10612021 - 财政年份:2021
- 资助金额:
$ 40.14万 - 项目类别:
Noninvasive sensory stimulation to promote glymphatic-lymphatic clearance for the treatment of Alzheimer’s Disease
无创感觉刺激促进类淋巴清除,治疗阿尔茨海默病
- 批准号:
10405043 - 财政年份:2021
- 资助金额:
$ 40.14万 - 项目类别:
Manipulating neural oscillations with non-invasive sensory stimulation for Alzheimer's disease intervention
通过非侵入性感觉刺激操纵神经振荡来干预阿尔茨海默病
- 批准号:
10228379 - 财政年份:2020
- 资助金额:
$ 40.14万 - 项目类别:
Targeting a Novel Regulator of Brain Aging and Alzheimer's Disease
针对大脑衰老和阿尔茨海默病的新型调节剂
- 批准号:
9321469 - 财政年份:2014
- 资助金额:
$ 40.14万 - 项目类别:
Examination of neural circuits underlying mood disorders in Alzheimer?s disease
阿尔茨海默病情绪障碍的神经回路检查
- 批准号:
8711599 - 财政年份:2014
- 资助金额:
$ 40.14万 - 项目类别:
Targeting a Novel Regulator of Brain Aging and Alzheimer's Disease
针对大脑衰老和阿尔茨海默病的新型调节剂
- 批准号:
8921933 - 财政年份:2014
- 资助金额:
$ 40.14万 - 项目类别:
Alzheimer's Disease Risk Genes in Human Microglia and Neurons Derived from iPSCs
人类小胶质细胞和 iPSC 神经元中的阿尔茨海默病风险基因
- 批准号:
8756320 - 财政年份:2014
- 资助金额:
$ 40.14万 - 项目类别:
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