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RNA Processing-Mediated Mechanisms of CNS Dysfunction in Myotonic Dystrophy

强直性肌营养不良中 CNS 功能障碍的 RNA 加工介导机制

基本信息

批准号：
10651422
负责人：
GARY J BASSELL
金额：
$ 7.29万
依托单位：
UNIVERSITY OF FLORIDA
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：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10651422
关键词：
3&apos Untranslated Regions Adult Affect Alternative Splicing Animal Model Antisense Oligonucleotides Autopsy Behavioral Biological Markers Biology Brain Brain imaging CUG repeat Cerebrospinal Fluid Childhood Clinical Trials Cognitive Complex Mixtures Defect Diagnosis Disease Disease Marker Disease Progression Dissection Dominant Genetic Conditions Dopamine D2 Receptor Down Syndrome Drowsiness Equilibrium Event Excitatory Synapse Exhibits Exons FDA approved Fatigue Fragile X Syndrome Functional disorder Future Gene Expression Profiling Genetic Diseases Glutamates Goals Heart Human Huntington Disease Image Impairment Inherited Inhibitory Synapse Knockout Mice Lead Link Measures Mediating Methods Modality Modeling Molecular Mus Muscle Muscle Weakness Muscle function Myotonia Myotonic Dystrophy NMDA receptor A1 Neuraxis Neurons Neurotransmitters Patients Persons Pharmaceutical Preparations Phenotype Physiological Play Polyadenylation Post-Transcriptional Regulation Prevalence Protein Isoforms Protein Kinase Proteins Public Health RNA RNA Processing RNA Splicing RNA-Binding Proteins Raclopride Research Role Skeletal Muscle Sleep disturbances Spliced Genes Symptoms Synapses Therapeutic Tissues Transcript Transgenic Mice Vertebrates Work autism spectrum disorder base behavioral phenotyping biomarker development biomarker-driven brain dysfunction brain tissue cell type clinical phenotype efficacy evaluation experience gamma-Aminobutyric Acid gene therapy genome-wide human data improved insight molecular phenotype mouse model nervous system disorder neurophysiology novel therapeutic intervention receptor restoration synaptic function targeted agent targeted treatment transcriptome transcriptome sequencing wasting

项目摘要

Myotonic dystrophy (dystrophia myotonica, DM) is an autosomal dominant genetic disease, with a diagnosed prevalence of 1:8000 people worldwide, that affects multiple tissues of the body, including skeletal muscle, heart, and related to this proposal, the central nervous system (CNS). DM1 is caused by expanded CTG repeats in the 3' UTR of dystrophia myotonica protein kinase (DMPK). There is substantial evidence in mouse DM1 models and human DM1 postmortem tissue to support an RNA-mediated disease mechanism where toxic intranuclear CUG RNA foci sequester Muscleblind (MBNL) RNA binding proteins that normally play crucial roles to regulate various aspects of post-transcriptional gene regulation. A major gap in our understanding is that we do not know which RNA processing defects underlie specific impairments in DM1 brain function. Recent work together with our new findings suggests that missplicing of RNAs encoding synaptic proteins is responsible for CNS dysfunction in DM1. Our central hypothesis is that CNS phenotypes are directly attributed to loss of MBNL mediated RNA processing and that restoration of MBNL activity and/or splicing can restore brain function. Our goal is to gain a thorough understanding of RNA processing-mediated mechanisms of CNS dysfunction in DM1 and use this to develop and rigorously evaluate novel therapeutic strategies. The overall objectives of this proposal are to use both candidate and genome wide approaches, applied to MBNL KO mice and a new AAV9 based neuronal mouse model, compared to RNAseq analysis of human postmortem brain, to evaluate the role of specific splicing events to drive symptoms, and to comprehensively identify changes in missplicing and RNA processing. Aim 1 will characterize how dysregulation of GABRG2, GRIN1, and SNAP25 splicing events is linked to molecular, cellular, and behavioral phenotypes observed in DM1. Aim 2 will develop a new AAV9 based mouse model to elucidate the set of RNA processing events in neurons that cause DM1 phenotypes, through transcriptional profiling and overlap of human DM brains with DM mouse model brains. Aim 3 will assess the extent to which antisense oligonucleotides or MBNL expression can rescue molecular, cellular, physiologic and behavioral phenotypes in DM1 mouse models. These studies will provide new mechanistic insights into how perturbations to specific RNA processing events can lead to CNS symptoms in myotonic dystrophy, and provide a broader comprehensive view of all transcriptome changes occurring in the DM CNS. The proposed work is significant, as no molecular changes have been linked to any phenotypes in the DM CNS. This provides the framework for future therapeutic efforts aimed at correcting CNS defects.

肌强直性营养不良症（肌强直性营养不良症，DM）是一种常染色体显性遗传病