Postsynaptic roles of ankyrins
锚蛋白的突触后作用
基本信息
- 批准号:10365120
- 负责人:
- 金额:$ 63.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ANK2 geneANK3 geneAnkyrin RepeatAnkyrinsAxonBehaviorBehavioralBiochemicalBioinformaticsBiological ProcessBiologyBipolar DisorderBrainBrain DiseasesCalciumCell membraneComplexDataDendritesDendritic SpinesDeubiquitinationDevelopmentFamily StudyFundingFunding OpportunitiesFutureGTP-Binding ProteinsGenomeGlutamatesHomer 1HumanHybridsImageIn VitroIntellectual functioning disabilityKnock-outKnockout MiceLaboratoriesMaintenanceMethodsMolecular and Cellular BiologyMorphologyMusMutationNeuraxisNeurobiologyNeurodevelopmental DisorderNeuronsPathogenicityPhenotypePlasmidsPlayPositioning AttributeProcessProteinsProteomicsReagentRegulationReporterResearchResolutionRodentRoleSchizophreniaSiteStructureSusceptibility GeneSynapsesSynaptosomesTestingTimeTransforming Growth Factor betaUnited States National Institutes of HealthVariantVertebral columnYeastsautism spectrum disordercell typeconditional knockoutendocannabinoid signalingexome sequencingfrontal lobegenome-widein vivomouse modelneuroproteomicsneuropsychiatric disordernovelpostsynapticrare variantrisk variantscaffoldspatiotemporalsynaptic functiontwo photon microscopy
项目摘要
ABSTRACT
Extensive evidence implicates glutamatergic synapses as key pathogenic sites in neuropsychiatric disorders
(NPDs). Recently-emerging evidence has implicated ankyrin proteins, including Ankyrin-G (AnkG),
encoded by the ANK3 gene, and Ankyrin-B (AnkB), encoded by ANK2, in the biology of central nervous
system synapses. While conventionally AnkG and –B have been seen as playing roles mainly at the axon
initial segment, their functions in central glutamatergic synapses have only begun to be investigated,
including in studies initiated by our laboratory. During the previous funding period, we have made extensive
progress in understanding the regulation and interactome of AnkG at synapses and in dendrites. Our
preliminary findings broaden our understanding of the neurobiology of ankyrins, and implicate them in
several novel process, including deubiquitination and endocannabinoid signaling. In this proposal we will
use neuroproteomics, conditional knockout and reporter mice, super-resolution and in vivo two-photon
microscopy, calcium imaging, bioinformatics, and behavioral analyses, to investigate the functions of
AnkG's protein partners in dendrite and at glutamatergic synapses. We hypothesize that AnkG performs
multiple novel functions including supramolecular scaffold complex maintenance and regulation of
endocannabinoid signaling, through which it controls spiny synapse development, structure, function, as
well as circuit level network activity and behavior, in a cell type and developmental period-specific manner.
We will test this hypothesis in the following Aims: Aim 1. To investigate the impact of cell type-dependent
and developmentally-timed knock out of AnkG on brain structure, function, and behavior across
maturation. Aim 2. To investigate the impact of cell type-dependent and developmentally-timed knock out
of AnkB on brain structure, function, and behavior across maturation. Aim 3. To determine the mechanisms
and functional significance of the interaction of AnkG with DAGLĮ. The proposed studies are highly novel
and impactful, given that the synaptic functions of ankyrins are only beginning to be investigated. This
proposal will be the first to investigate the function of several recently-discovered AnkG-interacting proteins
in unexpected biological processes, using multiple cutting edge methods, and will open new avenues for
many future studies.
摘要
大量证据表明谷氨酸能突触是神经精神疾病的关键致病部位
(NPDS)。最近出现的证据表明,包括Ankyrin-G(AnkG)在内的Ankyrin蛋白,
ANK3基因编码的Ankyrin-B和ANK2编码的Ankyrin-B(AnkB)在中枢神经生物学中
系统突触。传统上,AnkG和-B被认为主要在轴突起作用
最初的片段,它们在中枢谷氨酸能突触中的功能才刚刚开始研究,
包括我们实验室发起的研究。在上一次融资期间,我们取得了广泛的进展
AnkG在突触和树突中的调节和相互作用的研究进展。我们的
初步的发现加深了我们对Ankyrins神经生物学的理解,并将其与
一些新的过程,包括去泛素化和内源性大麻素信号。在本提案中,我们将
使用神经蛋白质组学、条件基因敲除和报告小鼠、超分辨率和体内双光子
显微镜、钙成像、生物信息学和行为分析,以研究
AnkG的蛋白质在树突和谷氨酸能突触中配对。我们假设AnkG执行
多种新功能,包括超分子支架复合体的维护和调节
内源性大麻素信号,通过它控制棘突触的发育、结构、功能,如
以及电路级网络活动和行为,以细胞类型和发育时期特定的方式。
我们将在以下目标中检验这一假说:目的1.调查细胞类型依赖的影响
AnkG基因敲除对大脑结构、功能和行为的影响
成熟。目的2.研究细胞类型依赖和发育时序基因敲除的影响
AnkB对大脑结构、功能和行为发育的影响。目标3.确定机制
以及AnkG与DAGLĮ相互作用的功能意义。拟议的研究是非常新颖的
考虑到对Anyrins的突触功能的研究才刚刚开始,这是很有影响力的。这
Proposal将首次研究最近发现的几种AnkG相互作用蛋白的功能
在意想不到的生物过程中,使用多种尖端方法,并将为
许多未来的研究。
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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Peter Penzes其他文献
Peter Penzes的其他文献
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{{ truncateString('Peter Penzes', 18)}}的其他基金
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10039790 - 财政年份:2020
- 资助金额:
$ 63.98万 - 项目类别:
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10250497 - 财政年份:2020
- 资助金额:
$ 63.98万 - 项目类别:
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10407640 - 财政年份:2020
- 资助金额:
$ 63.98万 - 项目类别:
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10626765 - 财政年份:2020
- 资助金额:
$ 63.98万 - 项目类别:
Adhesion molecules and developmental epilepsy disorders
粘附分子与发育性癫痫病
- 批准号:
10592736 - 财政年份:2017
- 资助金额:
$ 63.98万 - 项目类别:
Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia
精神分裂症树突棘可塑性异常的分子机制
- 批准号:
8287503 - 财政年份:2012
- 资助金额:
$ 63.98万 - 项目类别:
Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia
精神分裂症树突棘可塑性异常的分子机制
- 批准号:
8605620 - 财政年份:2012
- 资助金额:
$ 63.98万 - 项目类别:
Synaptic and dendritic dysfunction in psychiatric disorders
精神疾病中的突触和树突功能障碍
- 批准号:
9402750 - 财政年份:2012
- 资助金额:
$ 63.98万 - 项目类别:
Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia
精神分裂症树突棘可塑性异常的分子机制
- 批准号:
8431757 - 财政年份:2012
- 资助金额:
$ 63.98万 - 项目类别: