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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.

摘要