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

• 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
• 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

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.

项目总结