RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减

基本信息

批准号：
9973175
负责人：
Sami Barmada
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973175
关键词：
Affect Amyotrophic Lateral Sclerosis Animal Model Automobile Driving Binding CRISPR/Cas technology Cell Death Cells Cultured Cells Deposition Disease Disease model Equilibrium Feedback Foundations Frontotemporal Lobar Degenerations Genetic Transcription Genomics Goals High-Throughput Nucleotide Sequencing Homeostasis Human In Situ Individual Investigation Label Lead Maintenance Measures Mediating Messenger RNA Metabolism Methods Microscopy Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Neuroprotective Agents Pathogenesis Pathologic Pathway interactions Patients Physiologic pulse Process Prosencephalon RNA RNA Decay RNA Degradation RNA Helicase RNA chemical synthesis RNA metabolism RNA-Binding Proteins Reagent Regulation Role Series Spinal Cord Testing Therapeutic Time Transcript base defined contribution effective therapy fluorophore frontotemporal lobar dementia-amyotrophic lateral sclerosis genome editing improved in vivo evaluation induced pluripotent stem cell innovation longitudinal analysis neuron loss neuronal survival novel novel therapeutics overexpression prevent prospective protein TDP-43 survival prediction tool

项目摘要

Abstract Maintenance of RNA homeostasis involves a dynamic balance between RNA synthesis and turnover. This balance is critical for transcriptionally active cells such as neurons, as disruptions to any individual component can lead to RNA misprocessing and cell death. Our preliminary evidence indicates that deficiencies in RNA decay represent a fundamental and heretofore unrecognized mechanism driving neuronal dysfunction and death in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Our goals with this proposal are to elucidate the role of RNA decay in the pathogenesis of ALS and FTLD, and investigate a unique and promising therapeutic strategy affecting RNA decay. Based upon the results of initial studies, we propose that in ALS and the most common subtype of FTLD, characterized by neuronal deposits of the RNA binding protein TDP43, RNA homeostasis is disrupted by an inappropriate interaction between TDP43 and the RNA helicase UPF1, ultimately resulting in neurodegeneration. We will test this model by i) determining the impact of the TDP43-UPF1 interaction on neuronal survival and RNA decay, ii) evaluating if deficient RNA decay is sufficient and/or necessary for pathologic TDP43 deposition in neurons, and iii) assessing whether UPF1 expression improves neuronal survival by restoring TDP43 and RNA homeostasis. We will pursue these aims using a combination of longitudinal single-cell microscopy of human neurons derived from ALS and FTLD patients, CRISPR/Cas9 genome editing and high-throughput sequencing of pulse-labeled RNA. The multifaceted approach proposed here promises to uncover key pathways controlling neuronal survival in healthy cells and in those affected by ALS and FTLD, and will bring us one step closer to achieving our long-term goal of developing an effective treatment for these and other relentlessly progressive neurodegenerative disorders.

抽象的 RNA 稳态的维持涉及 RNA 合成和周转之间的动态平衡。这种平衡对于神经元等转录活性细胞至关重要，因为对任何个体的干扰成分可能导致 RNA 误加工和细胞死亡。我们的初步证据表明存在缺陷 RNA 衰变代表了驱动神经元功能障碍的基本且迄今为止未被认识的机制神经退行性疾病肌萎缩侧索硬化症 (ALS) 和额颞叶的死亡变性（FTLD）。我们提出这一提案的目标是阐明 RNA 衰变在发病机制中的作用 ALS 和 FTLD 的研究，并研究影响 RNA 衰减的独特且有前景的治疗策略。基于根据初步研究结果，我们建议在 ALS 和最常见的 FTLD 亚型中，以 RNA 结合蛋白 TDP43 的神经元沉积为特征，RNA 稳态被破坏 TDP43 和 RNA 解旋酶 UPF1 之间不适当的相互作用，最终导致神经变性。我们将通过 i) 确定 TDP43-UPF1 相互作用对神经元存活和 RNA 衰减，ii) 评估缺陷的 RNA 衰减是否足以和/或必要神经元中病理性 TDP43 沉积，以及 iii) 评估 UPF1 表达是否改善神经元通过恢复 TDP43 和 RNA 稳态来维持生存。我们将结合以下方式来实现这些目标：来自 ALS 和 FTLD 患者的人类神经元的纵向单细胞显微镜检查，CRISPR/Cas9 脉冲标记 RNA 的基因组编辑和高通量测序。提出的多方面方法这里有望揭示控制健康细胞和受感染细胞神经元存活的关键途径 ALS 和 FTLD，将使我们更接近实现开发有效的长期目标治疗这些和其他持续进行性神经退行性疾病。