RNA-mediated mechanisms of motor system dysfunction in spinal muscular atrophy

RNA介导的脊髓性肌萎缩症运动系统功能障碍的机制

基本信息

批准号：
10022699
负责人：
Livio Pellizzoni
金额：
$ 1.74万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022699
关键词：
Address Alternative Splicing Antisense Oligonucleotides Biogenesis Biology Cessation of life Data Defect Denervation Development Disease Disease model Etiology Event Functional disorder Gene Delivery Gene Expression Gene Targeting Genes Genetic Histones Human In Vitro Individual Infant Mortality Inherited Knowledge Link Mediating Messenger RNA Molecular Morphology Motor Motor Manifestations Motor Neuron Disease Motor Neurons Mus Mutation Neurodegenerative Disorders Neuromuscular Diseases Neurons Pathogenicity Pathology Pathway interactions Phenotype Play Population Post-Transcriptional Regulation Process RNA RNA Processing RNA Splicing Regulation Research Research Project Grants Role SMN protein (spinal muscular atrophy)SMN1 gene Sensory Small Nuclear Ribonucleoproteins Spinal Cord Spinal Muscular Atrophy Spliced Genes Synapses Synaptic Transmission System Systems Development TP53 gene Testing Therapeutic U7 Small Nuclear Ribonucleoprotein Up-Regulation Vitelliform macular dystrophy Wild Type Mouse cell type design disease phenotype in vivo insight mRNA Precursor motor disorder motor neuron degeneration mouse model neuromuscular neuron loss neurotransmission postnatal protein function restoration skeletal muscle wasting therapeutic development transcriptome transcriptome sequencing

项目摘要

Project Summary Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of motor neurons in the spinal cord and progressive atrophy of skeletal muscle. SMA is the most frequent inherited cause of infant mortality and no treatment is currently available for the disease. SMA is caused by a deficiency in the ubiquitously expressed survival motor neuron (SMN) protein due to homozygous deletion or mutation of the SMN1 gene. Despite a clear genetic basis of the disease and progress in the knowledge of SMN biology, the molecular mechanisms of SMA are poorly understood. SMN has a well- established function in the biogenesis of small nuclear ribonucleoproteins (snRNPs) that are critical for RNA splicing and 3' end formation of histone mRNAs. Moreover, it is becoming increasingly clear that SMN has additional functions in RNA regulation that might also contribute to SMA. However, although SMN plays a central role in post-transcriptional gene regulation, the contribution of specific SMN-dependent RNA pathways to SMA pathology remains elusive. A major challenge in SMA research is to identify which SMN-dependent RNA pathways and downstream genes among many potentially dysregulated events are directly relevant to the disease phenotype. This is critically important to elucidate the molecular mechanisms of this devastating disease and may also help to develop therapeutic approaches distinct from SMN upregulation. This project aims to determine the direct contribution of three specific and well-established SMN-dependent RNA pathways - U12 splicing, U7 snRNP biogenesis, and alternative splicing - to motor system dysfunction in a mouse model of the disease that provides the best recapitulation of the human condition both genetically and phenotypically. Our hypothesis is that specific defects in these pathways are causally linked to distinct functional abnormalities of the SMA motor system. To address this hypothesis, we will investigate both the role of disruption of each of these RNA pathways in SMA pathology and their requirement for normal motor system development using, respectively, selective restoration (Aim 1) and inhibition (Aim 2) approaches in mouse models. These studies will be combined with RNA profiling of select motor circuit neuron populations with the aim of identifying the transcriptome alterations induced by SMN deficiency that are specifically associated with each RNA pathway and their respective downstream gene targets that may directly contribute to the disease process, the functional relevance of which will be tested in SMA mice (Aim 3). Collectively, this project is designed to determine the RNA-dependent mechanisms of synaptic dysfunction and motor neuron death in SMA.

项目概要脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传性神经肌肉疾病，其特征是脊髓运动神经元退化和骨骼肌进行性萎缩。 SMA是最婴儿死亡的常见遗传原因，目前尚无针对该疾病的治疗方法。 SMA 是由于纯合子导致普遍表达的运动神经元存活蛋白 (SMN) 缺乏 SMN1基因缺失或突变。尽管该疾病有明确的遗传基础并且在治疗方面取得了进展由于对SMN生物学知识的了解，人们对SMA的分子机制知之甚少。 SMN 拥有良好的在对 RNA 至关重要的小核核糖核蛋白 (snRNP) 的生物合成中已确定功能组蛋白 mRNA 的剪接和 3' 末端形成。此外，越来越明显的是，SMN RNA 调节中的其他功能也可能有助于 SMA。不过，虽然SMN扮演着转录后基因调控的核心作用，特定 SMN 依赖性 RNA 途径的贡献 SMA 病理学仍然难以捉摸。 SMA 研究的一个主要挑战是确定哪些 SMN 依赖许多潜在失调事件中的 RNA 途径和下游基因与疾病表型。这对于阐明这种破坏性的分子机制至关重要疾病，也可能有助于开发不同于 SMN 上调的治疗方法。这个项目旨在确定三种特定且完善的 SMN 依赖性 RNA 途径的直接贡献 - U12 剪接、U7 snRNP 生物发生和选择性剪接 - 导致小鼠模型运动系统功能障碍该疾病在遗传和表型上提供了人类状况的最佳再现。我们的假设是这些途径中的特定缺陷与不同的功能异常存在因果关系 SMA 电机系统。为了解决这个假设，我们将研究每个的破坏作用 SMA 病理学中的这些 RNA 通路及其对正常运动系统发育的要求，分别在小鼠模型中采用选择性恢复（目标 1）和抑制（目标 2）方法。这些研究将与选定的运动回路神经元群体的 RNA 分析相结合，目的是识别 SMN 缺陷引起的转录组改变与每个 RNA 通路特异性相关以及它们各自可能直接促进疾病过程的下游基因靶标，其功能相关性将在 SMA 小鼠中进行测试（目标 3）。总的来说，该项目旨在确定 SMA 中突触功能障碍和运动神经元死亡的 RNA 依赖性机制。