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合成与周转之间的动态平衡。这种平衡对于转录活性细胞（例如神经元）至关重要，因为对任何个体的破坏成分可能导致RNA错误处理和细胞死亡。我们的初步证据表明缺陷在RNA中，衰减代表了驱动神经元功能障碍的基本和迄今未识别的机制和神经退行性疾病的死亡变性（FTLD）。我们通过该建议的目标是阐明RNA衰变在发病机理中的作用 ALS和FTLD，并研究了影响RNA衰变的独特而有希望的治疗策略。基于根据初步研究的结果，我们建议在ALS和FTLD的最常见亚型中 RNA结合蛋白TDP43的神经元沉积物的特征，RNA稳态受到了 TDP43和RNA解旋酶UPF1之间的不当相互作用，最终导致神经变性。我们将通过i）确定TDP43-UPF1相互作用的影响来测试此模型神经元存活和RNA衰变，ii）评估RNA衰减不足和/或必要的病理TDP43神经元中的沉积，iii）评估UPF1表达是否改善了神经元通过恢复TDP43和RNA稳态来生存。我们将使用组合来追求这些目标来自ALS和FTLD患者的人类神经元的纵向单细胞显微镜，CRISPR/CAS9 脉冲标记的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发现健康细胞中神经元存活的关键途径以及受 ALS和FTLD，将使我们更近一步，即实现我们的长期目标，即开发有效这些和其他无情进行性神经退行性疾病的治疗。