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

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

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GARY J BASSELL其他文献

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:
Project 1
项目1
  • 批准号:
    10271307
  • 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:
    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:
Project 1
项目1
  • 批准号:
    10678930
  • 财政年份:
    2020
  • 资助金额:
    $ 7.29万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10443847
  • 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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