Genome Stability in Glia & Disease

神经胶质细胞基因组稳定性

基本信息

批准号：
10522673
负责人：
PETER J MCKINNON
金额：
$ 45.5万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522673
关键词：
ATAC-seq Affect Applications Grants Architecture Astrocytes Base Excision Repairs Biology Brain Brain Neoplasms Cell physiology Cells Chromatin Critical Pathways Cytoplasmic Granules DNA Damage DNA Repair DNA Repair Disorder DNA Repair Pathway DNA strand break Data Defect Disease Disease model Engineering Event Excision Repair Functional disorder Gene Deletion Gene Expression Gene Mutation Genes Genetic Transcription Genome Genome Stability Genomic Instability Genotoxic Stress Germ-Line Mutation Goals Health Homeostasis Human Human Genome Inherited Knowledge Link Maintenance Microglia Modeling Molecular Conformation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurologic Neurons Nonhomologous DNA End Joining Oligodendroglia Pathogenesis Pathogenicity Pathway interactions Phosphoric Monoester Hydrolases Polynucleotide 5&apos -Hydroxyl-Kinase Population Predisposition Process Quality of life Research Ribonucleotides Role Signal Transduction Spinocerebellar Ataxias Syndrome Testing Therapeutic Therapeutic Intervention age related base brain health cell type cognitive ability experimental study genome integrity genomic locus genotoxicity homologous recombination human disease in vivo mouse model myelination nerve stem cell nervous system disorder nestin protein neuroinflammation neuron loss neuropathology novel oligodendrocyte lineage oxidative damage pseudotoxoplasmosis syndrome relating to nervous system repaired response spatiotemporal therapeutically effective therapy development transcriptome sequencing treatment strategy white matter

项目摘要

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.

抽象的基因组稳定对于人类健康至关重要。从众多的遗传综合症中可以看出这一点以DNA损伤反应有缺陷的特征。神经系统特别容易基因组损伤的后果以及涉及的大多数遗传DNA修复缺乏综合症神经变性，神经发育障碍或脑肿瘤。基因组完整性的维持不足越来越多地与更广泛的神经健康问题有关，包括与年龄相关的神经退行性问题具有认知能力和生活质量的事件。了解故障之间的机械连接因此，DNA损伤信号传导和人类疾病是基本的生物医学重要性。大多数研究处理基因组不稳定性相关的神经病理学专注于神经元丧失，例如对小脑颗粒或与各种脊椎小脑共济失调相关的Purkinje神经元。但是，其他功能基因组不稳定性相关的神经退行性综合症包括白质缺陷少突胶质细胞功能障碍。考虑到这些疾病中白质的宽度变化和减少，而且，大多数致病基因突变在整个神经系统中普遍表达其他神经胶质种群也很可能也受到影响。例如，神经炎症与星形胶质细胞和小胶质细胞激活还表征了由DNA修复缺陷引起的某些疾病。但是，直接调和神经胶质对基因组不稳定性综合症病理生物学的贡献的机理研究是疏。本应用程序中提出的实验将提供关键数据，以阐明神经胶质DNA损伤反应以及神经胶质如何促进疾病发病机理。我们建议利用新颖的鼠标模型神经退行性疾病，具有缺陷的DNA损伤信号传导，以确定临界DNA链断裂维修途径支持哺乳动物大脑中的神经胶质细胞功能。彼此之间，我们将评估 DNA损伤易感性的少突胶质细胞谱系确定这些神经胶质的功能障碍是如何发生的人基因组不稳定性综合征。还将使用少突胶质细胞对DNA损伤的反应进行评估染色质结构是遗传毒性敏感性的预测指标。最后，DNA损伤对小胶质细胞的影响将以缺陷的神经炎症性aicardigoutières综合征的新模型进行探讨核糖核苷酸惊喜维修。总的来说，这些数据将提供有关中央的关键信息维持神经胶质基因组的机制以及这些细胞中基因组不稳定性如何促进疾病发病。由于许多神经系统疾病的有效治疗干预变得可能成为可能现在，重要的是了解发生的全部变性变化。那是来自此提案的数据将提供一个重要的框架，以理解由基因组不稳定，并将为治疗策略提供依据。