Elucidating the roles of CACNA2D2 and CACNA2D3 in presynaptic regulation of mammalian synaptic function
阐明 CACNA2D2 和 CACNA2D3 在哺乳动物突触功能突触前调节中的作用
基本信息
- 批准号:10450212
- 负责人:
- 金额:$ 15.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAdhesionsAnimal ModelAtaxiaAuditoryAxonBrainBrain DiseasesBrain StemCellsCentral Nervous System DiseasesComplexDevelopmentDrug TargetingElectron MicroscopyEnterobacteria phage P1 Cre recombinaseEpilepsyEvoked PotentialsExtracellular ProteinFrequenciesFunctional disorderGenomeGlutamatesGoalsHumanIndividualIntellectual functioning disabilityIonsKnockout MiceKnowledgeMammalsMeasuresMetalsModelingMolecularMusMutationNeuraxisOutputPersonsPharmaceutical PreparationsPresynaptic TerminalsPropertyProtein IsoformsProteinsReagentRegulationRoleSchizophreniaSignal TransductionSiteSliceSpike PotentialSynapsesSynaptic TransmissionSynaptic VesiclesTherapeuticTransgenic MiceViral VectorVon Willebrand Factor A DomainWorkautism spectrum disorderbiophysical propertiesconditional knockoutgutless adenoviral vectorinsightmouse modelnervous system disorderneuronal circuitrynovelnovel therapeuticspatch clamppostsynapticpresynapticprogramsprotein protein interactionsynaptic functiontherapy developmenttraffickingvesicular releasevoltage
项目摘要
Project Summary/Abstract
Synapses are the fundamental unit of information transfer in the central nervous system (CNS)
and are composed a highly complex molecular machinery that tightly regulates synaptic
transmission and neuronal circuit output. A multitude of combinations of synaptic proteins and
their isoforms creates synapses with distinct functional properties to enable the broad diversity of
information encoding by neuronal circuits. Human mutations in synaptic proteins result in synaptic
dysfunction which causes neurological disorders such as schizophrenia, epilepsy, ataxia, autism,
and intellectual disability. Currently, 1.5 billion people worldwide suffer from a CNS disorder,
however there are limited therapeutic options. Therefore, elucidating the molecular mechanisms
that control synaptic function are fundamental to developing novel therapeutics for CNS disorders.
The α2δ proteins (α2δ 1-4) are extracellular proteins initially identified as auxiliary subunits of
voltage-gated Ca2+ (CaV) channel complexes and they are drug targets. However, multiple roles
have been described for the α2δ isoforms in independently regulating synaptic function and CaV
channel complexes. Human mutations specific to each α2δ isoform are correlated to distinct brain
disorders. Despite being highly expressed throughout the CNS and the clear linkage between
human mutations in α2δ2 and α2δ3 and CNS disorders, very little is known about the roles of
α2δ2 and α2δ3 in regulating synaptic function. In mammals, the globular bushy cells (GBCs) in
the auditory brainstem highly express both α2δ2 and α2δ3. The GBC axon gives rise to the calyx
of Held, a glutamatergic presynaptic terminal which is the sole input to drive action-potential (AP)
spiking and utilizes rapid, temporally precise AP signaling to encode auditory information. The
calyx is an exceptional model for gaining mechanistic insights into the presynaptic regulation of
synaptic function and neuronal circuit output Therefore our goal is to establish how presynaptic
α2δ2 and α2δ3 regulate synaptic function and neuronal circuit output. We will use novel
transgenic mouse models and viral vectors to manipulate the α2δ2 and α2δ3 at the calyx during
different developmental stages and analyze how their loss impact synaptic transmission and
neuronal circuit output.. Ultimately, our findings will provide fundamental insights into how
information is encoded by the CNS and will facilitate the development of treatments for a wide
range of neurological disorders due to α2δ2 and α2δ3 mutations. Finally, our novel animal models
will be valuable reagents to the Illuminating the Druggable Genome (IDG) program
项目摘要/摘要
突触是中枢神经系统(CNS)信息传递的基本单位
它们组成了一个高度复杂的分子机制,严密地调节突触
传输和神经元电路输出。突触蛋白和突触蛋白的多种组合
它们的异构体创造了具有不同功能属性的突触,从而使
通过神经元回路对信息进行编码。人类突触蛋白突变导致突触
导致精神分裂症、癫痫、共济失调、自闭症等神经系统疾病的功能障碍,
和智力残疾。目前,全球有15亿人患有中枢神经系统疾病,
然而,治疗选择有限。因此,阐明其发生的分子机制
控制突触功能是开发治疗中枢神经系统疾病的新疗法的基础。
α2δ蛋白(α2δ1-4)是最初确定的辅助亚单位的胞外蛋白。
电压门控钙离子(Cav)通道复合体是药物靶点。然而,多个角色
已经描述了α2δ亚型独立调节突触功能和腔静脉
通道复合体。每个α2δ亚型特有的人类突变与不同的大脑相关
精神错乱。尽管在整个中枢神经系统中都高度表达,而且
人类在α-2、δ-2和α-2-δ-3和中枢神经系统疾病中的突变,对其作用知之甚少
α-2-δ-2和α-2-δ-3在突触功能调节中的作用在哺乳动物中,球状丛状细胞(GBCs)
听性脑干高表达α-2-δ-2和α-2-δ-3。
Hold,谷氨酸能突触前终末,是驱动动作电位(AP)的唯一输入。
尖峰,并利用快速的,时间上精确的AP信号来编码听觉信息。这个
Calyx是一种特殊的模型,可以获得对突触前调节的机械性见解
突触功能和神经元回路输出因此我们的目标是确定突触前如何
α-2-δ-2和α-2-δ-3调节突触功能和神经元回路输出。我们将使用小说
转基因小鼠模型和病毒载体在花萼中操纵α2δ2和α2δ3
并分析它们的丢失如何影响突触传递和
神经元回路输出..最终,我们的发现将为我们提供基本的见解
信息由中枢神经系统编码,并将促进广泛治疗的发展
α2δ2和α2δ3突变导致的一系列神经疾病。最后,我们的新动物模型
将是阐明可药物基因组(IDG)计划的有价值的试剂
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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Samuel Matthew Young其他文献
Samuel Matthew Young的其他文献
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{{ truncateString('Samuel Matthew Young', 18)}}的其他基金
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
- 批准号:
10524734 - 财政年份:2019
- 资助金额:
$ 15.45万 - 项目类别:
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
- 批准号:
10302979 - 财政年份:2019
- 资助金额:
$ 15.45万 - 项目类别:
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
- 批准号:
10057401 - 财政年份:2019
- 资助金额:
$ 15.45万 - 项目类别:
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
- 批准号:
9884425 - 财政年份:2019
- 资助金额:
$ 15.45万 - 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
- 批准号:
9479765 - 财政年份:2015
- 资助金额:
$ 15.45万 - 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
- 批准号:
10194445 - 财政年份:2015
- 资助金额:
$ 15.45万 - 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
- 批准号:
10401920 - 财政年份:2015
- 资助金额:
$ 15.45万 - 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
- 批准号:
10621329 - 财政年份:2015
- 资助金额:
$ 15.45万 - 项目类别:
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