TAOK2 Kinase Signaling in Human Neural Stem Cell Development
TAOK2 Kinase Signaling in Human Neural Stem Cell Development
批准号:
10531206
负责人:
Smita Yadav
金额:
$44.25万
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
项目状态:
已结题
起止时间:
2019-12-02 至 2024-11-30
关键词:
16p11.23-DimensionalAffectBiochemicalBiological AssayBiological ModelsBiologyBrainCRISPR/Cas technologyCell Differentiation processCell LineCentriolesCentrosomeCiliaClinicalComplexCopy Number PolymorphismDataDefectDevelopmentDiseaseDissectionEventFRAP1 geneFluorescenceFunctional disorderFutureGenesGeneticGrowthHumanHuman DevelopmentHuman EngineeringImageKnock-outLengthMapsMass Spectrum AnalysisMediatingMental disordersMethodologyMicroscopyMolecularMothersMutationNeurodevelopmental DisorderNeuronsNeurosphereOrganoidsOutcomePathogenesisPathologyPathway interactionsPatientsPhosphorylationPhosphotransferasesProtein-Serine-Threonine KinasesProteinsProteomeProteomicsResearch ProposalsRoleSamplingSignal PathwaySignal TransductionStem Cell DevelopmentStructural defectStructureSusceptibility GeneSynapsesTechniquesTestingWorkautism spectrum disorderbasechemical geneticscilium biogenesisclinical diagnosisdomain mappingendophenotypeexperimental studygain of function mutationgenetic risk factorgenome editinggenomic locushuman diseaseinduced pluripotent stem cellinduced pluripotent stem cell technologyinnovationinsightloss of functionnerve stem cellnervous system disorderneurodevelopmentneurogenesisneuron developmentneuropathologyneuroregulationnovel therapeutic interventionnull mutationpatient variabilitysensorstem cell modelstem cell proliferationstem cell technologysuperresolution imagingsuperresolution microscopyultra high resolution
中文摘要
越来越多的证据表明,神经干细胞增殖和早期神经发生中的异常
与神经发育和精神障碍的发病机制密切相关。尽管
与几种神经疾病的病理生理学有关,人类基因组通过的机制
控制神经发生及其功能障碍在疾病中的表现仍然是该领域的主要空白
神经发育生物学。在这项提案中,我们将研究自闭症易感基因的作用,
TAOK2编码一种丝氨酸苏氨酸激酶,与人类神经干细胞的发育和功能有关。两者都有
功能丧失和激活的TAOK2突变与自闭症谱系障碍(ASD)有关。
此外,TAOK2是16p11.2基因组座位上的基因之一,其拷贝数变异(CNV)是
与ASD相关的最普遍的遗传风险因素。虽然我们和其他人的工作证明了
令人信服的证据表明,TAOK2对于神经元和突触的发育是重要的,TAOK2在
人类神经前体细胞(NPC)的发育和分化尚未被研究过。此外,
TAOK2在与16p11.2拷贝数变异相关的病理过程中的作用尚不清楚。基于
我们初步发现的力量,这项研究建议的中心假设是TAOK2激酶
在中心体上协调一个信号中枢,调节人类神经前体干细胞的发育,
这一信号通路的紊乱参与了ASD的发病机制。我们将阐明它的作用
利用2D和3D人诱导多能干细胞模型研究TAOK2在鼻咽癌发育中的作用
(目标1)。接下来,将确定TAOK2调节纤毛生长和信号传递的机制
使用超分辨率成像和生化方法(AIM2)。TAOK2在睫状体中的作用
16p11.2缺失和复制携带者患者来源的鼻咽癌中观察到的缺陷将被确定
通过应用定量蛋白质组学和基因组编辑技术(Aim3)。利用一种组合
创新方法和与人类疾病相关的模型系统,我们试图理解TAOK2如何
激酶信号转导神经干细胞发育,以及其信号通路的扰动
有助于16p11.2CNV的临床神经病理。
好了!
英文摘要
Increasing evidence indicates that aberrations in neural stem cell proliferation and early neurogenesis
are critically involved in the pathogenesis of neurodevelopmental and psychiatric disorders. Despite being
implicated in pathophysiology of several neurological diseases, the mechanisms through which human kinome
controls neurogenesis and how its dysfunction manifests in disease remain major gaps in the field of
neurodevelopmental biology. In this proposal, we will investigate the role of an autism susceptibility gene,
TAOK2, which encodes a serine threonine kinase, in human neural stem cell development and function. Both
loss-of-function and activating TAOK2 mutations have been associated with autism spectrum disorders (ASD).
Further, TAOK2 is one of the genes in the 16p11.2 genomic locus, copy number variation (CNV) of which is
the most prevalent genetic risk factor associated with ASD. While work by us and others has demonstrated
compelling evidence that TAOK2 is important for neuronal and synaptic development, the role of TAOK2 in
human neural progenitor cell (NPC) development and differentiation has not been investigated. Further, the
contribution of TAOK2 in the pathology associated with 16p11.2 copy number variation is unknown. Based on
the strength of our preliminary findings, the central hypothesis of this research proposal is that TAOK2 kinase
orchestrates a signaling hub at the centrosome that regulates human neural progenitor stem cell development,
and that perturbation of this signaling pathway contributes to pathogenesis of ASD. We will elucidate the role of
TAOK2 in NPC development through use of 2D and 3D human induced pluripotent stem cell (hiPSC) models
(Aim1). Next, mechanisms through which TAOK2 regulates ciliary growth and signaling will be determined
using super-resolution imaging and biochemical approaches (Aim2). The contribution of TAOK2 in the ciliary
defects observed in patient-derived NPCs from 16p11.2 deletion and duplication carriers will be determined
through application of quantitative proteomics and genome editing techniques (Aim3). Utilizing a combination
of innovative approaches and human disease relevant model systems, we seek to understand how TAOK2
kinase signaling mediates neural stem cell development, and how perturbations in its signaling pathways
contribute to the clinical neuropathology of 16p11.2 CNV.
!
期刊论文(0)
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科研奖励(0)
会议论文
Kinase Dysfunction in Autism and Neurodevelopmental Disorders
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批准号:10657059
-
项目类别:
-
资助金额:$72.22万
-
财政年份:2023
-
负责人:Smita Yadav
-
依托单位:
TAOK2 Kinase Signaling in Human Neural Stem Cell Development
-
批准号:10302304
-
项目类别:
-
资助金额:$44.25万
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财政年份:2019
-
负责人:Smita Yadav
-
依托单位:
TAOK2 Kinase Signaling in Human Neural Stem Cell Development
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批准号:10064147
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项目类别:
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资助金额:$44.99万
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财政年份:2019
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负责人:Smita Yadav
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依托单位:
Role of Autism Susceptibility Gene, TAOK2 kinase, and its novel substrates in Synaptogenesis
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批准号:9146973
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项目类别:
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资助金额:$12.1万
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财政年份:2015
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负责人:Smita Yadav
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依托单位:
海外基金