Tubulin Mutations in Neuronal Migration Disorders
神经元迁移障碍中的微管蛋白突变
基本信息
- 批准号:8517751
- 负责人:
- 金额:$ 46.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesAnimal ModelBehaviorBindingBiochemicalBiologicalBiological AssayBiological ModelsBrainCell-Free SystemCellsCognitiveComplexComputing MethodologiesCultured CellsDataDefectDevelopmentDiseaseEmbryoEnvironmentEscherichia coliEventFailureGenesHistocytochemistryHomologous GeneHumanIn VitroInduced MutationKnock-in MouseLeadMammalsMapsMeasuresMethodsMicrotubule-Associated ProteinsMicrotubulesMolecularMolecular ChaperonesMonitorMultigene FamilyMusMutationMutation SpectraNeuronal Migration DisorderNeuronsPathway interactionsPatternPlayPolymerasePopulationProcessPropertyProtein BindingProteinsRattusRecombinantsResolutionRoleStructureTestingTimeTissuesTransgenic AnimalsTransgenic MiceTubulinWorkbasechaperonin CCTcytosolic chaperonindisabilitydisease-causing mutationin vivomigrationmouse modelmutantpolypeptideresearch study
项目摘要
DESCRIPTION (provided by applicant): Microtubules are assembled from ¿/¿ tubulin heterodimers. In mammals, a small multigene family encodes ¿- and ¿-tubulins, with each gene product (termed an isotype) having a distinct developmentally regulated and tissue-specific pattern of expression. Recently, mutations have been identified in genes (e.g. TUBA1A and TUBB2B) encoding these isotypes that cause certain human neuronal migration disorders, all of which are associated with severe cognitive disabilities. These discoveries reinforce the notion that microtubule based events play a central role in neuronal migration during brain development, and that disruption of critical microtubule processes results in cortical dysgeneses. Analysis of the properties of disease causing mutations in TUBA1A suggests two broad classes of mechanism: 1. Defects in the complex tubulin heterodimer assembly pathway This pathway involves sequential interactions of newly synthesized ¿- and ¿-tubulin polypeptides with multiple chaperone proteins (including the cytosolic chaperonin CCT and five tubulin specific chaperones, TBCA-TBCE). CCT facilitates productive folding by providing a sequestered environment in which folding can occur in the absence of off-pathway interactions that might otherwise lead to aggregation, while the tubulin specific chaperones function downstream of CCT as an ¿/¿ tubulin heterodimer assembly machine. 2. Defective microtubule dynamics and/or interactions with Microtubule Associated Proteins (MAPs) Disease causing mutations might compromise microtubule dynamics or interfere with interaction(s) between microtubules and MAPs that are critical for directing proper neuronal migration. The experiments proposed here constitute a multifaceted approach towards understanding the mechanism of these diseases. 1) We will exploit the mutation-induced defective interactions between CCT-generated ¿-tubulin folding intermediates and TBCB to define this interaction. These experiments will establish the mechanism of action of TBCB as a critical player in proper corticogenesis. 2) We will generate populations of isotypically homogeneous wild type and mutant tubulin heterodimers. These will be used to identify MAPs (such as the microtubule polymerase TOGp) that bind differently to microtubules polymerized from wild type and disease-causing mutant heterodimers. 3) For those disease-causing tubulin mutations that do not interfere with the heterodimer assembly machinery, we will examine their effect on microtubule dynamics in single cell experiments (including cultured neurons) in vivo. 4) The mechanism of disease will be explored via the construction and analysis of transgenic mice in which one copy of wild type tuba1a (the mouse homolog of TUBA1A) is replaced with the same allele harboring a disease-causing mutation. The brains of these mice will be examined in terms of their development and the behavior of their microtubules in vitro and in vivo.
描述(由申请人提供):微管由微管蛋白异源二聚体组装而成。在哺乳动物中,一个小的多基因家族编码<$-和<$-微管蛋白,每个基因产物(称为同种型)具有不同的发育调节和组织特异性表达模式。最近,已经在编码这些同种型的基因(例如TUBA 1A和TUBB 2B)中鉴定出突变,这些突变导致某些人类神经元迁移障碍,所有这些都与严重的认知障碍相关。这些发现强化了这样的观点:基于微管的事件在大脑发育期间的神经元迁移中发挥着核心作用,并且关键微管过程的破坏会导致皮质发育不良。对TUBA 1A中致病突变的性质的分析表明了两大类机制:1.复杂微管蛋白异二聚体组装途径中的缺陷该途径涉及新合成的<$-和<$-微管蛋白多肽与多种伴侣蛋白(包括胞质伴侣蛋白CCT和五种微管蛋白特异性伴侣蛋白,TBCA-TBCE)的顺序相互作用。CCT通过提供隔离的环境来促进生产性折叠,其中折叠可以在不存在否则可能导致聚集的途径外相互作用的情况下发生,而微管蛋白特异性伴侣蛋白在CCT下游作为微管蛋白异二聚体组装机器起作用。2.缺陷微管动力学和/或与微管相关蛋白(MAP)的相互作用引起疾病的突变可能会损害微管动力学或干扰微管和MAP之间的相互作用,这对指导正确的神经元迁移至关重要。这里提出的实验构成了一个多方面的方法来了解这些疾病的机制。1)我们将利用突变诱导的缺陷CCT产生的微管蛋白折叠中间体和TBCB之间的相互作用来定义这种相互作用。这些实验将确立TBCB作为适当皮质生成中的关键参与者的作用机制。2)我们将产生同种型同质野生型和突变微管蛋白异源二聚体的群体。这些将用于鉴定与从野生型和致病突变异源二聚体聚合的微管不同地结合的MAP(如微管聚合酶TOGp)。3)对于那些不干扰异二聚体组装机制的致病微管蛋白突变,我们将在体内单细胞实验(包括培养的神经元)中研究它们对微管动力学的影响。4)将通过构建和分析转基因小鼠来探索疾病的机制,其中野生型tuba 1a(TUBA 1A的小鼠同源物)的一个拷贝被携带致病突变的相同等位基因取代。这些小鼠的大脑将在体外和体内的发育和微管的行为方面进行检查。
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)
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NICHOLAS COWAN其他文献
NICHOLAS COWAN的其他文献
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{{ truncateString('NICHOLAS COWAN', 18)}}的其他基金
Tubulin Mutations in Neuronal Migration Disorders
神经元迁移障碍中的微管蛋白突变
- 批准号:
8661847 - 财政年份:2013
- 资助金额:
$ 46.06万 - 项目类别:
Tubulin Mutations in Neuronal Migration Disorders
神经元迁移障碍中的微管蛋白突变
- 批准号:
8672657 - 财政年份:2012
- 资助金额:
$ 46.06万 - 项目类别:
Tubulin Mutations in Neuronal Migration Disorders
神经元迁移障碍中的微管蛋白突变
- 批准号:
8293824 - 财政年份:2012
- 资助金额:
$ 46.06万 - 项目类别:
Role of alpha-Tubulin Mutations in Lissencephaly
α-微管蛋白突变在无脑畸形中的作用
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7862424 - 财政年份:2009
- 资助金额:
$ 46.06万 - 项目类别:
Inhibition of the Tubulin Folding Pathway as a Novel Therapy for Cancer
抑制微管蛋白折叠途径作为癌症的新疗法
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7608641 - 财政年份:2007
- 资助金额:
$ 46.06万 - 项目类别:
Inhibition of the Tubulin Folding Pathway as a Novel Therapy for Cancer
抑制微管蛋白折叠途径作为癌症的新疗法
- 批准号:
7615339 - 财政年份:2007
- 资助金额:
$ 46.06万 - 项目类别:
Inhibition of the Tubulin Folding Pathway as a Novel Therapy for Cancer
抑制微管蛋白折叠途径作为癌症的新疗法
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7450805 - 财政年份:2007
- 资助金额:
$ 46.06万 - 项目类别:
Inhibition of the Tubulin Folding Pathway as a Novel Therapy for Cancer
抑制微管蛋白折叠途径作为癌症的新疗法
- 批准号:
7321819 - 财政年份:2007
- 资助金额:
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