Role of DNA double-strand breaks in neural function and homeostasis

项目摘要/摘要 与衰老相关的大脑疾病，包括认知能力下降，是公共卫生面临的最大挑战之一。 DNA修复正在成为与年龄相关的认知衰退和神经退化的潜在调节因素，并且 可能是未来有效治疗策略的一个强大的潜在靶点。大脑可能是脆弱的 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变化 神经细胞类型的周转和长寿命。这表明基因组维持途径对 大脑健康：持续或错误修复的DNA双链断裂(DSB)可能会对基因组产生影响 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修复在脑生理学中的作用尚未得到解决。这个 这一根本的知识差距的广泛含义是发展的关键机会 治疗和预防脑部疾病的疗法可能会被遗漏。这提供了一个强有力的理由 从多个水平阐明神经元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脑功能和脑功能的影响 精神错乱。我们将阐明神经回路功能与经典的非同源的关系 神经元随年龄增长的末端连接(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双链在成熟期断裂形成和修复 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失活在神经元中的后果 细胞和基因组水平；(2)阐明衰老和C-NHEJ失活对神经细胞表观基因组的影响 以及，(3)确定老化和C-NHEJ修复对电路水平神经元生理学的影响。这个 建议的方法包括对基因组上的神经元功能进行全面、多学科的分析， 表观基因组、生物体和神经回路水平。拟议的项目意义重大，因为它使用了创新的 研究对人类大脑健康有重大影响的新兴概念的方法，与年龄有关 认知功能减退和神经退行性疾病。此外，该项目将导致新的 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相关的其他领域的知识。

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.