Role of DNA double-strand breaks in neural function and homeostasis
DNA 双链断裂在神经功能和稳态中的作用
基本信息
- 批准号:10241955
- 负责人:
- 金额:$ 33.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAffectAgeAge-associated memory impairmentAgingAnimalsBiological AssayBiologyBrainBrain DiseasesCellsCerebral cortexChromatin StructureDNADNA Double Strand BreakDNA RepairDNA Sequence AlterationDementiaDetectionDevelopmentDiseaseDouble Strand Break RepairERG geneEconomic BurdenElectrophysiology (science)Epigenetic ProcessFutureGene ExpressionGenesGenomeGenome StabilityGenomicsGoalsHeadHippocampus (Brain)HistologicHomeostasisHumanImpaired cognitionIn VitroKnowledgeLongevityMaintenanceMediatingMissionModelingMosaicismMusNatural regenerationNerve DegenerationNeurobiologyNeurodegenerative DisordersNeuronal PlasticityNeuronsNeurophysiology - biologic functionNonhomologous DNA End JoiningOpticsOrganizational ChangePathway interactionsPhenotypePhysiologicalPhysiologyPositioning AttributePreventionProcessPublic HealthResearchResearch ProposalsRoleSleepStructureTechniquesTechnologyTestingTimeUnited States National Institutes of Healthaging brainawakebrain healthcell typecognitive functionepigenomeepigenomicsgenetic approachgenetic manipulationimprovedinnovationinsightinterdisciplinary approachmultidisciplinaryneural circuitneurobehavioral testneurophysiologypreventrelating to nervous systemrepairedtargeted sequencingtheoriestherapeutic developmenttherapeutically effectivetooltranscriptome
项目摘要
PROJECT SUMMARY/ABSTRACT
Aging-associated brain disorders, including cognitive decline, are among the greatest public health challenges.
DNA repair is emerging as a potential regulator of age-related cognitive decline and neurodegeneration, and
may be a powerful potential target for effective therapeutic strategies in the future. The brain may be vulnerable
to genomic alterations due to its network structure, the complexity of its transcriptome, and the low or absent
turnover and long lifespan of neural cell types. This suggests genome maintenance pathways are crucial for
brain health: persistent or incorrectly repaired DNA double-strand breaks (DSBs) could contribute to genomic
alterations, thus promoting age-related cognitive impairment and neurodegenerative disorders. However, the
role of post-developmental, neuronal DSB repair in brain physiology with age has not been addressed. The
broad implication for this fundamental gap in knowledge is that crucial opportunities for development of
therapeutics for treatment and prevention of brain disorders may be missed. This provides a strong rationale for
elucidating the biology of neuronal DSB repair at multiple levels. Thus, our long-term goal is to determine the
extent to which neuronal DNA double-strand break formation and repair impact brain function and brain
disorders. We will elucidate the relationship between neural circuit function and the classical non-homologous
end-joining (C-NHEJ) DNA repair machinery in neurons with age. Moreover, we will elucidate the extent to which
post-developmental, neuronal DSB repair suppresses brain aging phenotypes related to chromatin structure,
genome organization, and gene expression.
The central hypothesis of the proposed project is that DNA double-strand break formation and repair in mature
neurons impacts neural physiology. To test this hypothesis and to advance toward our long-term goal, we
propose the following specific aims: (1) Define consequences of aging and C-NHEJ inactivation in neurons at
the cellular and genomic level; (2) Elucidate impact of aging and C-NHEJ inactivation on the neuronal epigenomic
landscape; and, (3) Determine impact of aging and C-NHEJ repair on circuit-level neuronal physiology. The
proposed approach involves a comprehensive, multidisciplinary analysis of neuronal function at the genomic,
epigenomic, organismal, and neural circuit level. The proposed project is significant because it uses innovative
approaches to investigate emerging concepts with major implications for human brain health, age-related
cognitive decline, and neurodegenerative diseases. Further, the project will lead to the development of new
research tools and models. Insights gained from the proposed studies are also expected to inform research and
knowledge in other fields related to genomic stability and aging.
项目摘要/摘要
与衰老相关的脑疾病(包括认知能力下降)是最大的公共卫生挑战之一。
DNA修复正在成为与年龄相关的认知下降和神经变性的潜在调节剂,并且
将来可能是有效治疗策略的强大潜在目标。大脑可能很脆弱
由于其网络结构,转录组的复杂性以及低或不存在的基因组改变
神经细胞类型的营业额和寿命长。这表明基因组维持途径对于
大脑健康:持续或错误地修复的DNA双链断裂(DSB)可能有助于基因组
改变,从而促进与年龄相关的认知障碍和神经退行性疾病。但是,
尚未解决发展后神经元DSB修复在脑生理中随着年龄的增长的作用。这
对知识的这一根本差距的广泛意义是发展的关键机会
可能会错过治疗和预防脑部疾病的治疗剂。这为
阐明多个级别的神经元DSB修复的生物学。因此,我们的长期目标是确定
神经元DNA双链断裂的形成和修复影响大脑功能和大脑的范围
疾病。我们将阐明神经回路函数与经典非同学之间的关系
随着年龄的增长,神经元中的末端加入(C-NHEJ)DNA修复机械。此外,我们将阐明
发育后的神经元DSB修复抑制与染色质结构有关的脑老化表型,
基因组组织和基因表达。
拟议项目的中心假设是DNA双链断裂的形成和成熟的修复
神经元影响神经生理。为了检验这一假设并迈向我们的长期目标,我们
提出以下具体目的:(1)定义在神经元中衰老和C-NHEJ失活的后果
细胞和基因组水平; (2)阐明衰老和C-NHEJ失活对神经元基因组学的影响
景观; (3)确定衰老和C-NHEJ修复对电路级神经元生理的影响。这
提出的方法涉及对基因组神经元功能的全面,多学科分析,
表观基因组,生物和神经回路水平。拟议的项目很重要,因为它使用创新
调查新兴概念的方法,对人脑健康有重大影响,与年龄有关
认知能力下降和神经退行性疾病。此外,该项目将导致新的发展
研究工具和模型。从拟议的研究中获得的见解也有望为研究和
与基因组稳定性和衰老有关的其他领域的知识。
项目成果
期刊论文数量(0)
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{{ truncateString('Kira Poskanzer', 18)}}的其他基金
Role of DNA double-strand breaks in neural function and homeostasis
DNA 双链断裂在神经功能和稳态中的作用
- 批准号:
10414105 - 财政年份:2020
- 资助金额:
$ 33.11万 - 项目类别:
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- 资助金额:
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