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: 10241955
• 负责人: Kira Poskanzer
• 金额: $ 33.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10241955
• 关键词: 3-Dimensional; Address; Affect; Age; Age-associated memory impairment; Aging; Animals; Biological Assay; Biology; Brain; Brain Diseases; Cells; Cerebral cortex; Chromatin Structure; DNA; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; Dementia; Detection; Development; Disease; Double Strand Break Repair; ERG gene; Economic Burden; Electrophysiology (science); Epigenetic Process; Future; Gene Expression; Genes; Genome; Genome Stability; Genomics; Goals; Head; Hippocampus (Brain); Histologic; Homeostasis; Human; Impaired cognition; In Vitro; Knowledge; Longevity; Maintenance; Mediating; Mission; Modeling; Mosaicism; Mus; Natural regeneration; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Nonhomologous DNA End Joining; Optics; Organizational Change; Pathway interactions; Phenotype; Physiological; Physiology; Positioning Attribute; Prevention; Process; Public Health; Research; Research Proposals; Role; Sleep; Structure; Techniques; Technology; Testing; Time; United States National Institutes of Health; aging brain; awake; brain health; cell type; cognitive function; epigenome; epigenomics; genetic approach; genetic manipulation; improved; innovation; insight; interdisciplinary approach; multidisciplinary; neural circuit; neurobehavioral test; neurophysiology; prevent; relating to nervous system; repaired; targeted sequencing; theories; therapeutic development; therapeutically effective; tool; transcriptome

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.

项目概要/摘要 与衰老相关的脑部疾病，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衰退和神经退行性疾病的潜在调节剂，并且 可能是未来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缺失而导致的基因组改变 神经细胞类型的更新和长寿命。这表明基因组维护途径对于 大脑健康：持续或不正确修复的 DNA 双链断裂 (DSB) 可能会导致基因组损伤 改变，从而促进与年龄相关的认知障碍和神经退行性疾病。然而， 随着年龄的增长，发育后神经元 DSB 修复在大脑生理学中的作用尚未得到解决。这 这种知识上的根本差距的广泛含义是，发展的重要机会 可能会错过治疗和预防脑部疾病的疗法。这提供了强有力的理由 从多个层面阐明神经元 DSB 修复的生物学。因此，我们的长期目标是确定 神经元 DNA 双链断裂形成和修复对大脑功能和大脑的影响程度 失调。我们将阐明神经回路功能与经典非同源神经网络之间的关系 随着年龄的增长，神经元中的末端连接（C-NHEJ）DNA修复机制。此外，我们将阐明在多大程度上 发育后神经元 DSB 修复抑制与染色质结构相关的大脑衰老表型， 基因组组织和基因表达。 该项目的中心假设是DNA双链断裂在成熟细胞中形成和修复。 神经元影响神经生理学。为了检验这一假设并朝着我们的长期目标前进，我们 提出以下具体目标：（1）定义衰老和 C-NHEJ 神经元失活的后果 细胞和基因组水平； (2) 阐明衰老和C-NHEJ失活对神经元表观基因组的影响 景观; (3) 确定衰老和 C-NHEJ 修复对回路水平神经元生理学的影响。这 所提出的方法涉及对基因组神经元功能进行全面的多学科分析， 表观基因组、有机体和神经回路水平。拟议的项目意义重大，因为它采用了创新 研究对人类大脑健康、年龄相关的重大影响的新兴概念的方法 认知能力下降和神经退行性疾病。此外，该项目将导致新的开发 研究工具和模型。从拟议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相关的其他领域的知识。