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:
- 金额:$ 7.29万
- 依托单位:
- 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:
- 关键词:3&apos Untranslated RegionsAdultAffectAlternative SplicingAnimal ModelAntisense OligonucleotidesAutopsyBehavioralBiological MarkersBiologyBrainBrain imagingCUG repeatCerebrospinal FluidChildhoodClinical TrialsCognitiveComplex MixturesDefectDiagnosisDiseaseDisease MarkerDisease ProgressionDissectionDominant Genetic ConditionsDopamine D2 ReceptorDown SyndromeDrowsinessEquilibriumEventExcitatory SynapseExhibitsExonsFDA approvedFatigueFragile X SyndromeFunctional disorderFutureGene Expression ProfilingGenetic DiseasesGlutamatesGoalsHeartHumanHuntington DiseaseImageImpairmentInheritedInhibitory SynapseKnockout MiceLeadLinkMeasuresMediatingMethodsModalityModelingMolecularMusMuscleMuscle WeaknessMuscle functionMyotoniaMyotonic DystrophyNMDA receptor A1NeuraxisNeuronsNeurotransmittersPatientsPersonsPharmaceutical PreparationsPhenotypePhysiologicalPlayPolyadenylationPost-Transcriptional RegulationPrevalenceProtein IsoformsProtein KinaseProteinsPublic HealthRNARNA ProcessingRNA SplicingRNA-Binding ProteinsRacloprideResearchRoleSkeletal MuscleSleep disturbancesSpliced GenesSymptomsSynapsesTherapeuticTissuesTranscriptTransgenic MiceVertebratesWorkautism spectrum disorderbasebehavioral phenotypingbiomarker developmentbiomarker-drivenbrain dysfunctionbrain tissuecell typeclinical phenotypeefficacy evaluationexperiencegamma-Aminobutyric Acidgene therapygenome-widehuman dataimprovedinsightmolecular phenotypemouse modelnervous system disorderneurophysiologynovel therapeutic interventionreceptorrestorationsynaptic functiontargeted agenttargeted treatmenttranscriptometranscriptome sequencingwasting
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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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GARY J BASSELL的其他文献
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{{ truncateString('GARY J BASSELL', 18)}}的其他基金
Single-Molecule Imaging of Ubiquitination Dynamics in Neurons
神经元泛素化动力学的单分子成像
- 批准号:
10817362 - 财政年份:2023
- 资助金额:
$ 7.29万 - 项目类别:
Mechanism and Function Of MBNL Mediated mRNA Localization in Neuronal Development and Neurologic Disease
MBNL介导的mRNA定位在神经元发育和神经系统疾病中的机制和功能
- 批准号:
10553695 - 财政年份:2020
- 资助金额:
$ 7.29万 - 项目类别:
Mechanism and Function Of MBNL Mediated mRNA Localization in Neuronal Development and Neurologic Disease
MBNL介导的mRNA定位在神经元发育和神经系统疾病中的机制和功能
- 批准号:
10334425 - 财政年份:2020
- 资助金额:
$ 7.29万 - 项目类别:
Dysregulated nascent proteome in human FX neuron
人类 FX 神经元新生蛋白质组失调
- 批准号:
10842046 - 财政年份:2020
- 资助金额:
$ 7.29万 - 项目类别:
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
- 批准号:
10213864 - 财政年份:2019
- 资助金额:
$ 7.29万 - 项目类别:
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
- 批准号:
10405913 - 财政年份:2019
- 资助金额:
$ 7.29万 - 项目类别:
RNA processing-mediated mechanisms of CNS dysfunction in Myotonic Dystrophy
RNA加工介导强直性肌营养不良中枢神经系统功能障碍的机制
- 批准号:
10055974 - 财政年份:2019
- 资助金额:
$ 7.29万 - 项目类别:
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