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G-quadruplex Structures as Targets and Tools in ALS

G-四联体结构作为 ALS 的靶标和工具

基本信息

批准号：
9143821
负责人：
Pavel Ivanov
金额：
$ 22.19万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9143821
关键词：
Amyotrophic Lateral Sclerosis Apoptosis Apoptotic Base Sequence Biological Process C9ORF72 Cell Line Cellular biology Cessation of life Characteristics Cytoplasmic Granules Cytostatics DNA DNA Structure Development Disease Drug usage Frontotemporal Dementia G-Quartets Gene Expression Genes Genetic Health Injury Introns Laboratories Lead Libraries Link Literature Mediating Molecular Molecular Biology Motor Neuron Disease Motor Neurons Mutation Nerve Degeneration Neurodegenerative Disorders Neuroprotective Agents Oligonucleotides Outcomes Research Pathogenesis Pathway interactions Patients Physiological Play Post-Transcriptional Regulation Property Proteins RNA Reporting Ribonucleases Role Stress Structure Testing Therapeutic Transcript Transfer RNA Translations analog angiogenin base biological adaptation to stress cytotoxicity insight loss of function medical schools motor neuron degeneration neuron loss neuroprotection novel synthetic construct targeted treatment tool

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that currently has no cure. We propose to investigate the roles of G-quadruplex (G4) structures and G4-assembling molecules in neurodegeneration and ALS pathogenesis. G4s are unique structures associated with multiple biological processes including genetic instability, transcriptional and post-transcriptional regulation of gene expression. We have previously identified novel stress response pathway, which is triggered by the ribonuclease angiogenin (ANG) by cleavage of cytoplasmic tRNA molecules to produce tRNA-derived stress-induced RNAs (tiRNAs). In turn, selective tiRNAs that are capable of assembling G4 structures (G4-tiRNAs) protect motor neurons from stress-induced injuries and death. This neuroprotection is achieved by the ability of G4-tiRNAs to reprogram gene expression on post-transcriptional level and by promotion of Stress Granules (SGs), pro- survival RNA granules implicated in the pathogenesis of ALS. Significantly, the disease-associated hexameric GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (C9-FTD/ALS). Number of studies has shown that C9ORF72 transcripts with pathological G4C2 repeats (referred as RNA-G4C2 or rG4C2) significantly contribute to the development of C9-FTD/ALS. We and others have recently discovered that rG4C2 repeats assemble G4s. We hypothesize here that G4s play important regulatory roles, which are altered upon their amplification (such as observed during G4C2 expansion). Understanding of the physiological roles of G-quadruplexes in the context of neurodegeneration will provide important insights into the cellular and molecular mechanisms of ALS, and will evaluate novel G4- based therapeutic approaches for the treatment of motor neuron disease.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前无法治愈。我们建议研究 G 四链体 (G4) 结构和 G4 组装分子在神经退行性变和 ALS 发病机制中的作用。 G4 是与多种生物过程相关的独特结构，包括遗传不稳定性、基因表达的转录和转录后调控。我们之前已经发现了一种新的应激反应途径，该途径是由核糖核酸酶血管生成素（ANG）通过裂解细胞质 tRNA 分子产生 tRNA 衍生的应激诱导 RNA（tiRNA）而触发的。反过来，能够组装 G4 结构的选择性 tiRNA (G4-tiRNA) 可以保护运动神经元免受压力引起的损伤和死亡。这种神经保护作用是通过 G4-tiRNA 在转录后水平重编程基因表达的能力以及通过促进应激颗粒 (SG)（参与 ALS 发病机制的促生存 RNA 颗粒）来实现的。值得注意的是，C9ORF72 基因第一个内含子中与疾病相关的六聚体 GGGGCC (G4C2) 重复扩增是额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症 (C9-FTD/ALS) 最常见的遗传原因。大量研究表明，具有病理性 G4C2 重复序列（称为 RNA-G4C2 或 rG4C2）的 C9ORF72 转录本对 C9-FTD/ALS 的发展有显着贡献。我们和其他人最近发现 rG4C2 重复组装 G4。我们在此假设 G4 发挥重要的调节作用，这些作用在其扩增时发生改变（例如在 G4C2 扩增期间观察到的）。了解 G-四链体在神经变性中的生理作用将为了解 ALS 的细胞和分子机制提供重要见解，并将评估用于治疗运动神经元疾病的新型基于 G4 的治疗方法。