CircRNAs and CNS Gene Transfer

CircRNA 和 CNS 基因转移

基本信息

批准号：
9898485
负责人：
Aravind Asokan
金额：
$ 37.58万
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/9898485
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 Expression Profiling 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：圆形RNA（CIRCRNA）是一类新兴的RNA分子，由于其对核酸外切的核酸酶的无法访问，其可能会长时间表达。最近解剖circrna生物发生的研究发现了倒重复序列，例如人类中的Alu重复序列，两侧是大量受圆形外显子的影响，并显示了这些顺式元素以及拼接机械对于它们的循环化至关重要。在哺乳动物的大脑中，circrnas似乎高度丰富，并且受发展和可塑性的动态调节。特别是，它们似乎在突触和神经元分化和发育过程中富含。尽管取得了令人兴奋的进步，但仍未用于研究大脑中合成CIRCRNA的生物发生和神经系统疾病的模型。 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）。能够破坏这些小鼠模型中看到的神经毒性RNA焦点的CIRCRNA可能会为FTD/ALS设计治疗，其中C9ORF72膨胀很普遍，并且认为是造成病因。总体而言，当前的建议将有助于制定新的策略，以有效地在动物模型中生物发生CIRCRNA，这可能有助于理解影响哺乳动物大脑中Circrna生物发生的因素，并迎来了基于圆环RNA的新型核酸疗法。