Genome Stability in Glia & Disease

摘要 基因组稳定性对人类健康至关重要。这一点从众多的遗传性人类综合征中可见一斑。 以DNA损伤反应缺陷为特征。神经系统特别容易患上 基因组损伤的后果，以及大多数遗传性DNA修复缺陷综合征包括 神经退行性变、神经发育障碍或脑瘤。基因组完整性的缺陷维护 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变 损害认知能力和生活质量的事件。了解故障之间的机械联系 因此，DNA损伤信号和人类疾病具有基本的生物医学重要性。大多数研究 处理基因组不稳定相关的神经病理学集中在神经元丢失上，如对 小脑颗粒或浦肯野神经元与各种脊髓小脑性共济失调相关。然而，其他功能 与基因组不稳定相关的神经退行性综合征包括脑白质缺陷，由 少突胶质细胞功能障碍。鉴于这些疾病中白质的广泛改变和减少， 而且大多数致病基因突变在神经系统中普遍表达，这是 很可能其他神经胶质细胞也会受到影响。例如，与星形胶质细胞和 小胶质细胞的激活也是由DNA修复缺陷引起的某些疾病的特征。但是，直接 协调神经胶质细胞在基因组不稳定综合征病理生物学中的作用的机制研究是 稀疏。本申请中提出的实验将为阐明胶质细胞dna损伤提供关键数据。 以及神经胶质细胞在疾病发病机制中的作用。我们建议利用新的鼠标模型 具有DNA损伤信号缺陷的神经退行性疾病确定关键的DNA链断裂 修复哺乳动物大脑中支持神经胶质细胞功能的通路。因此，我们将评估 少突胶质细胞系DNA损伤易感性确定这些胶质细胞功能障碍是如何发生在 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 将在一种由缺陷引起的神经炎性艾卡迪·古蒂埃综合征的新模型中进行探索 核糖核酸切除修复。总的来说，这些数据将提供有关中央银行的关键信息 维持神经胶质细胞基因组的机制以及这些细胞的基因组不稳定如何导致疾病 发病机制。随着对许多神经疾病的有效治疗干预成为可能，它 现在对了解所发生的退化变化的全谱至关重要。因此，这项提案中的数据 将为理解由以下原因引起的神经系统疾病的进展方面提供重要的框架 基因组不稳定，并将为治疗策略提供参考。

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.