CircRNAs and CNS Gene Transfer

CircRNA 和 CNS 基因转移

基本信息

批准号：
10158515
负责人：
Aravind Asokan
金额：
$ 37.57万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158515
关键词：
Affect Age Animal Model Animals Antisense RNA Astrocytes Biogenesis Brain Brain region C9ORF72 Cell Culture Techniques Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Data Detection Development Disease Dose Elements Endoribonucleases Engineering Exons Exonuclease Gene Expression Gene Expression Regulation Gene Transfer Genes Genetic Translation Growth Factor Heart Hepatotoxicity Human In Vitro Insulin Internal Ribosome Entry Site Inverted Repeat Sequences Liver Mediating MicroRNAs Mus Neuroglia Neurological Models Neuronal Differentiation Neurons Outcome Patients Plasmids Population Pre-Clinical Model Production RNA RNA Processing RNA Splicing Recombinant adeno-associated virus (rAAV)Safety Synapses System Testing Therapeutic Tissues Toxic effect Transaminases Translations Treatment Efficacy Untranslated RNA Work adeno-associated viral vector base cell age cell type circular RNA design frontotemporal lobar dementia-amyotrophic lateral sclerosis gene therapy clinical trial improved mRNA Stability mouse model nervous system disorder neuron development neurotoxic neurotoxicity novel nucleic acid-based therapeutics overexpression protein expression public health relevance response small hairpin RNA therapeutic protein time interval vector vector genome

项目摘要

ABSTRACT: Circular RNAs (circRNAs) are an emerging class of RNA molecules with potential for prolonged expression due to their inaccessibility to exonucleases. Recent studies dissecting circRNA biogenesis have found inverted repeat sequences such as ALU repeats in humans, flanking a large number of exons that are subject to circularization and have shown these cis-elements as well as splicing machinery are essential for their circularization. In the mammalian brain, circRNAs appear to be highly abundant and dynamically regulated by development and plasticity. In particular, they appear to be enriched at the synapses and during neuronal differentiation and development. Despite these exciting advances, no systems for studying biogenesis of synthetic circRNAs in the brain and models of neurological disease. Specific aims for the current proposal are focused on engineering circRNA expression systems, studying factors affecting circRNA biogenesis efficiency in the brain, and utilizing these systems to interrogate deregulation of splicing and RNA-induced neurotoxicity seen in a C9orf72 Hexanucleotide Repeat Expansion mouse model of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). CircRNAs capable of disrupting the neurotoxic RNA foci seen in these mouse models may enable design of therapeutics for FTD/ALS, where the C9orf72 expansion is prevalent and believed to be causative. Overall, the current proposal will help develop new strategies for efficient biogenesis of circRNAs in animal models, which are likely to help understand factors affecting circRNA biogenesis in the mammalian brain as well as usher in a new class of nucleic acid therapeutics based on circular RNAs.

摘要：环状 RNA (circRNA) 是一类新兴的 RNA 分子，由于它们无法被核酸外切酶所接近，因此具有延长表达的潜力。最近剖析 circRNA 生物发生的研究发现，反向重复序列（例如人类中的 ALU 重复序列）位于大量易于环化的外显子两侧，并表明这些顺式元件以及剪接机制对其环化至关重要。在哺乳动物大脑中，circRNA 似乎非常丰富，并受到发育和可塑性的动态调节。特别是，它们似乎在突触以及神经元分化和发育过程中富集。尽管取得了这些令人兴奋的进展，但还没有用于研究大脑中合成 circRNA 的生物发生和神经疾病模型的系统。当前提案的具体目标集中于设计 circRNA 表达系统，研究影响大脑中 circRNA 生物合成效率的因素，并利用这些系统来研究在额颞叶痴呆的 C9orf72 六核苷酸重复扩增小鼠模型中观察到的剪接失调和 RNA 诱导的神经毒性。（FTD）和肌萎缩侧索硬化症（ALS）。能够破坏这些小鼠模型中观察到的神经毒性 RNA 灶的 CircRNA 可能有助于设计 FTD/ALS 疗法，其中 C9orf72 扩增很普遍，并被认为是其致病原因。总体而言，当前的提案将有助于开发在动物模型中有效实现 circRNA 生物发生的新策略，这可能有助于了解影响哺乳动物大脑中 circRNA 生物发生的因素，并引入一类基于环状 RNA 的新型核酸疗法。