Molecular Mechanisms of Purkinje Cell Degeneration in Ataxia-Telangiectasia

共济失调毛细血管扩张症浦肯野细胞变性的分子机制

基本信息

  • 批准号:
    10193587
  • 负责人:
  • 金额:
    $ 46.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2023-09-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Ataxia-telangiectasia (A-T) is an autosomal recessive, multi-system, disorder caused by mutations in the universally expressed ataxia-telangiectasia, mutated (ATM) gene affecting approximately 1:40,000-1:100,000 births, for which there is no cure. Characterized by progressive cerebellar neurodegeneration, there are no effective treatments for A-T, with patients succumbing to chronic sinopulmonary infections or A-T related cancer by the third decade of life. Furthermore, the cause of cerebellar neurodegeneration, chiefly affecting Purkinje cells (PCs), the primary output neuron of the cerebellum, has remained elusive since the first descriptions of A- T nearly 80 years ago, largely because mouse models do not recapitulate the human cerebellar phenotype of PC death. Thus, the critical objectives of this proposal are to develop the first human A-T model system that recapitulates the cerebellar phenotype and to use that system to identify molecular differences between patient and unaffected PCs as well as differences between human and mouse PCs. Toward that end, we will use our recently published protocol (Buchholz et al, 2020) to generate an induced pluripotent stem cell (iPSC) model system and use that system to study the effects of A-T patient mutations on developing human PCs. Using our protocol, we have been able to differentiate cerebellar Purkinje cells that match young adult PCs on a transcriptomic level (Buchholz et al., 2020) and fire specific calcium currents in co-culture with their target neurons, granule cells (GCs). Our specific aims in this proposal are therefore to use this protocol to differentiate iPSCs derived from patients with A-T, as well as unaffected control iPSCs derived from family members, into PCs to study A-T PC phenotypes, including defects in survival and synaptic function in co-culture with GCs. To discover molecular changes in Purkinje cells with the A-T mutation, we will study global gene expression and protein phosphorylation compared to controls. Critically, we will then use CRISPR-Cas9 prime editing to correct the ATM mutation and test for rescue, including identifying key changes in rescued versus mutant gene expression and proteomics. Taken together, these studies will identify pathways involved in A-T PC phenotypes and will discover altered pathways that could provide novel targets for therapy.
项目总结

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)
专利数量(0)

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Mary Elizabeth Hatten其他文献

Mary Elizabeth Hatten的其他文献

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{{ truncateString('Mary Elizabeth Hatten', 18)}}的其他基金

A Bioengineering Approach to Develop a Laminar 3D Cerebellar Neuronal Circuit for Modeling Human Cerebellum
开发用于模拟人类小脑的层状 3D 小脑神经元回路的生物工程方法
  • 批准号:
    10444198
  • 财政年份:
    2022
  • 资助金额:
    $ 46.61万
  • 项目类别:
A Bioengineering Approach to Develop a Laminar 3D Cerebellar Neuronal Circuit for Modeling Human Cerebellum
开发用于模拟人类小脑的层状 3D 小脑神经元回路的生物工程方法
  • 批准号:
    10604377
  • 财政年份:
    2022
  • 资助金额:
    $ 46.61万
  • 项目类别:
Chromatin Changes During CNS Migration and Circuit Formation
中枢神经系统迁移和回路形成过程中染色质的变化
  • 批准号:
    10017341
  • 财政年份:
    2019
  • 资助金额:
    $ 46.61万
  • 项目类别:
Development of a model system to study human cerebellar neurons
开发研究人类小脑神经元的模型系统
  • 批准号:
    9066826
  • 财政年份:
    2015
  • 资助金额:
    $ 46.61万
  • 项目类别:
Development of a model system to study human cerebellar neurons
开发研究人类小脑神经元的模型系统
  • 批准号:
    8954174
  • 财政年份:
    2015
  • 资助金额:
    $ 46.61万
  • 项目类别:
Role of mPAR6 Polarity CNS Neuronal Migration
mPAR6 极性中枢神经系统神经元迁移的作用
  • 批准号:
    7352740
  • 财政年份:
    2006
  • 资助金额:
    $ 46.61万
  • 项目类别:
Role of Cdc42 and Par6 Polarity Complex in CNS Neuronal Migration
Cdc42 和 Par6 极性复合物在 CNS 神经元迁移中的作用
  • 批准号:
    8187605
  • 财政年份:
    2006
  • 资助金额:
    $ 46.61万
  • 项目类别:
Role of Cdc42 and Par6 Polarity Complex in CNS Neuronal Migration
Cdc42 和 Par6 极性复合物在 CNS 神经元迁移中的作用
  • 批准号:
    8627650
  • 财政年份:
    2006
  • 资助金额:
    $ 46.61万
  • 项目类别:
Role of mPAR6 Polarity CNS Neuronal Migration
mPAR6 极性中枢神经系统神经元迁移的作用
  • 批准号:
    7569420
  • 财政年份:
    2006
  • 资助金额:
    $ 46.61万
  • 项目类别:
Role of mPAR6 Polarity CNS Neuronal Migration
mPAR6 极性中枢神经系统神经元迁移的作用
  • 批准号:
    7761699
  • 财政年份:
    2006
  • 资助金额:
    $ 46.61万
  • 项目类别:

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ATM 信号通路中新型蛋白磷酸酶的鉴定
  • 批准号:
    8224187
  • 财政年份:
    2009
  • 资助金额:
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  • 项目类别:
Identification of Novel Protein Phosphatases in the ATM Signaling Pathway
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  • 批准号:
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  • 项目类别:
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  • 财政年份:
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