Genome Stability in Glia & Disease

摘要 基因组稳定性对人类健康至关重要。这是显而易见的从众多的遗传人类综合征 其特征在于有缺陷的DNA损伤反应。神经系统特别容易出现 基因组损伤的后果，大多数遗传性DNA修复缺陷综合征涉及 神经变性、神经发育障碍或脑肿瘤。基因组完整性的维护缺陷 也越来越多地与更广泛的神经健康问题联系在一起，包括与年龄相关的神经退行性疾病 损害认知能力和生活质量的事件。理解故障之间的机械联系 因此，DNA损伤信号传导和人类疾病具有基本的生物医学重要性。大多数研究 处理与基因组不稳定性相关的神经病理学关注神经元损失，例如对 与各种脊髓小脑共济失调相关的小脑颗粒或浦肯野神经元。然而，其他特征 与基因组不稳定性相关的神经退行性综合征包括白色物质缺陷， 少突胶质细胞功能障碍考虑到这些疾病中白色物质的广泛改变和减少， 大多数致病基因突变在整个神经系统中普遍存在， 其他神经胶质细胞群也很可能受到影响。例如，神经炎症与星形胶质细胞和 小胶质细胞活化也是由DNA修复缺陷引起的某些疾病的特征。然而，直接 协调神经胶质对基因组不稳定综合征病理生物学作用的机制研究， 稀疏。本实验将为阐明胶质细胞DNA损伤提供关键数据 反应和神经胶质细胞如何有助于疾病的发病机制。我们建议利用新的小鼠模型， 神经退行性疾病与缺陷的DNA损伤信号，以确定关键的DNA链断裂 支持哺乳动物大脑中神经胶质细胞功能的修复途径。因此，我们将评估 少突胶质细胞谱系的DNA损伤易感性，以确定这些胶质细胞中的功能障碍如何发生， 人类基因组不稳定综合征少突胶质细胞对DNA损伤的反应也将使用 染色质结构作为遗传毒性易感性的预测因子。最后，DNA损伤对小胶质细胞的影响 将在一个新的模型中探索神经炎性AparthodiGoutières综合征， 核苷酸切除修复。总的来说，这些数据将提供有关中央 维持神经胶质基因组的机制以及这些细胞中基因组的不稳定性如何导致疾病 发病机制随着对许多神经系统疾病的有效治疗干预成为可能， 现在对于了解发生的退行性变化的全部范围至关重要。因此，本提案中的数据 将提供一个重要的框架，了解神经系统疾病的进展方面所造成的 基因组的不稳定性，并将告知治疗策略的治疗。

Abstract Genome stability is essential for human health. This is apparent from the multitude of inherited human syndromes characterized by defective DNA damage responses. The nervous system is particularly prone to the consequences of genome damage, and most inherited DNA repair deficiency syndromes involve neurodegeneration, neurodevelopmental disorders or brain tumors. Defective maintenance of genome integrity is also increasingly being linked to broader neurologic health issues, including age-related neurodegenerative events that mar cognitive ability and quality of life. Understanding the mechanistic connections between faulty DNA damage signaling and human disease is therefore of fundamental biomedical importance. Most studies dealing with genome instability associated neuropathology focus on neuronal loss, such as the impact on cerebellar granule or Purkinje neurons associated with various spinocerebellar ataxias. However, other features of genome instability associated neurodegenerative syndromes include white matter defects, resulting from oligodendrocyte dysfunction. Given the widespread alterations and reduction in white matter in these diseases, and that most disease-causing gene mutations are ubiquitously expressed throughout the nervous system, it’s very likely that other glial populations are also affected. For instance, neuroinflammation linked to astrocyte and microglia activation also characterize certain diseases caused by DNA repair defects. However, direct mechanistic studies to reconcile the contribution of glia to the pathobiology of genome instability syndromes are sparse. The experiments proposed in this application will provide key data illuminating the glial DNA damage response and how glia contribute to disease pathogenesis. We propose leveraging novel mouse models of neurodegenerative disease with defective DNA damage signaling to determine the critical DNA strand break repair pathways that support glial cell function in the mammalian brain. Accordingly, we will evaluate the oligodendrocyte lineage for DNA damage susceptibility to determine how dysfunction in these glia occur in human genome instability syndromes. Oligodendrocyte responses to DNA damage will also be assessed using chromatin architecture as a predictor of genotoxic susceptibility. Finally, the impact of DNA damage on microglia will be explored in a new model of the neuroinflammatory Aicardi Goutières Syndrome resulting from defective ribonucleotide excision repair. Collectively, these data will provide critical information regarding the central mechanisms that maintain the glial genome and how genome instability in these cells contribute to disease pathogenesis. As effective therapeutic intervention for many neurological diseases is becoming possible, it’s now critical to understand the full spectrum of degenerative changes that occur. Thus, data from this proposal will provide an important framework for understanding progressive aspects of neurological disease resulting from genome instability and will inform therapeutic strategies for treatment.