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
- 来源:
- 关键词:ATM Gene MutationATM Signaling PathwayATM geneAffectAtaxia TelangiectasiaAtaxia Telangiectasia PatientsBiological AssayBiological ModelsBirthCRISPR/Cas technologyCalciumCell DeathCell SurvivalCellsCellular AssayCerebellar degenerationCerebellumCessation of lifeChronicCoculture TechniquesControl GroupsDNA DamageDataData SetDefectDevelopmentDiseaseEtiologyFamily memberFibroblastsFire - disastersFunctional disorderGene ExpressionGene ProteinsGenesGenetic DiseasesHumanImageImmunologic Deficiency SyndromesInfectionLifeLive BirthLymphocyteMalignant NeoplasmsMessenger RNAMethodsMitochondriaModelingMolecularMorphologyMusMutationNerve DegenerationNeurologicNeuronsOutputOxidative StressPathway interactionsPatientsPhenotypePhosphorylationPredispositionProteinsProteomicsProtocols documentationPublishingPurkinje CellsResearchRoleSpecificitySystemTechniquesTelangiectasisTestingTuberous Sclerosisataxia telangiectasia mutated proteincell typecomparativeeffective therapyexperimental studygranule cellhuman diseasehuman embryonic stem cellinduced pluripotent stem cellinsightmouse modelmutantmutation correctionnew therapeutic targetphosphoproteomicsresponsesingle-cell RNA sequencingstem cell differentiationstem cell modelsynaptic functionsynaptogenesistranscriptometranscriptomicsyoung adult
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)
专著数量(0)
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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