Investigating the synaptic pathology of Autism
研究自闭症的突触病理学
基本信息
- 批准号:10053341
- 负责人:
- 金额:$ 54.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-01 至 2022-10-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAgonistAnimal ModelAnimalsBehaviorBehavioralBindingCharacteristicsChemicalsChemosensitizationCo-ImmunoprecipitationsComplexDNA Sequence AlterationDataDiseaseDrug TargetingEquilibriumFeedbackFragile X SyndromeGene MutationGene ProteinsGenesGenetic ModelsGenetic studyGlutamate ReceptorGlutamatesGoalsHomeostasisKnock-outLinkLongevityMeasurementMetabotropic Glutamate ReceptorsModelingMolecularMorphologyMutationN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeurodevelopmental DisorderNeuronsOrganismOutputPathogenesisPathologicPathologyPatternPharmaceutical PreparationsPhysiologicalProcessProtein EngineeringProteinsPublishingRiskScienceSignal TransductionSliceStereotypingStructureSynapsesSystemTechnologyTestingTherapeuticTranslatingUBE3A geneVariantautism spectrum disorderbasedesigngene productgraph theoryin vitro Assayinformation processinginsightkinase inhibitorlink proteinmathematical modelmembermouse modelnetwork modelsnew technologynoveloverexpressionpredictive modelingprotein complexprotein functionresponsescaffoldsmall moleculestemsynaptic functiontargeted treatmenttherapeutic targettooltransmission processvector
项目摘要
PROJECT SUMMARY
Genetic mutations that confer autism risk often occur in genes that are expressed at the glutamate synapse.
The protein products of these genes form a highly interconnected protein interaction network (PIN), and
represent attractive therapeutic targets since they are expressed throughout the lifespan and can be acutely
targeted with small molecule drugs. However, the dynamic, network-scale behavior of this PIN in normal or
disease states is poorly understood. Here, we apply a novel PIN-mapping technology, quantitative multiplex
co-immunoprecipitation, to explore the input-output relationships of an autism-linked PIN at the glutamate
synapse as it responds to physiological inputs. Our target system is a 20-member PIN, consisting of glutamate
receptors, scaffolds, and signal transduction molecules; mutations in the genes encoding all target proteins
have been genetically linked to autism. We first show that, in wild-type animals, our target PIN changes its
pattern of co-associations in a stereotyped manner in response to acute stimulation with KCl or glutamate,
using cultured neurons or acute slices. We then model the input-output relationships of the PIN system, and
demonstrate that the PIN produces specific, recognizable signatures in response to stimulation through the
mGluR or NMDA receptors. In the context of physiological glutamate stimulation, the PIN integrates the two
inputs to produce a coordinated cellular response- potentiation or de-potentiation. Based on these and other
preliminary observations and published data, we propose that mutations that contribute to autism risk disrupt
information flow through this PIN, such that the balance between LTP-like potentiation and LTD-like
depotentiaion is altered, ultimately leading to an organism-level imbalance between excitation and inhibition.
We will test this hypothesis by modeling the PIN response to mGluR or NMDA stimulation in three distinct,
well-characterized animal models of autism- the Fragile X knockout, Shank3 knockout, and Ube3a
overexpressing models. We will characterize the input-output relationships for mGluR or NMDA stimulation,
and mathematically model their integration using a vector transformation model in principal component space.
We will define specific mechanisms by which autism-linked mutations disrupt either input-output relationships,
or disrupt signal integration in the context of physiological stimulation. In addition, we will treat two of our
animal models (Shank3 and Fragile X) with drugs that have been previously demonstrated to rescue autism-
like behaviors. We will model the response of the PIN to the drug with or without concurrent stimulation to
define a PIN signature associated with behavioral rescue. In summary we propose to (1) define normal
information flow through a PIN consisting of the protein products of autism-liked genes; (2) define how
information flow is disrupted in mouse models of autism, with the goal of understanding the system sufficiently
to design targeted drug treatments and (3) define how the PIN responds to drugs that correct behavior, which
could serve as a template for the design of PIN-modifying treatments to restore normal synaptic function.
项目摘要
导致自闭症风险的基因突变通常发生在谷氨酸突触上表达的基因中。
这些基因的蛋白质产物形成高度互连的蛋白质相互作用网络(PIN),并且
代表有吸引力的治疗靶点,因为它们在整个生命周期中表达,
以小分子药物为靶点。然而,在正常或
疾病状态知之甚少。在这里,我们应用一种新的PIN定位技术,定量多重
免疫共沉淀,探索孤独症相关的PIN在谷氨酸的输入-输出关系。
神经突触对生理输入作出反应。我们的目标系统是一个由20个成员组成的PIN,
受体、支架和信号转导分子;编码所有靶蛋白的基因突变
与自闭症有遗传联系我们首先表明,在野生型动物中,我们的目标PIN改变了其
以刻板方式响应KCl或谷氨酸盐急性刺激的共缔合模式,
使用培养的神经元或急性切片。然后,我们对PIN系统的输入输出关系进行建模,
证明PIN产生特定的,可识别的签名,以响应刺激,通过
mGluR或NMDA受体。在生理性谷氨酸刺激的背景下,PIN整合了这两个
输入以产生协调的细胞反应-增强或去增强。基于这些和其他
根据初步观察和已发表的数据,我们提出,导致自闭症风险的突变破坏了
信息流过该PIN,使得LTP样增强和LTD样增强之间的平衡
去电位被改变,最终导致兴奋和抑制之间的生物体水平的不平衡。
我们将通过在三个不同的,
特征明确的自闭症动物模型-脆性X基因敲除、Shank 3基因敲除和Ube 3a
过度表达模型我们将描述mGluR或NMDA刺激的输入-输出关系,
并在主成分空间中使用矢量变换模型对它们的积分进行数学建模。
我们将定义自闭症相关突变破坏输入-输出关系的具体机制,
或者在生理刺激的情况下破坏信号整合。此外,我们将把我们的两个
动物模型(Shank 3和Fragile X)与先前已被证明可以挽救自闭症的药物,
比如行为我们将模拟PIN对药物的反应,有或没有同时刺激,
定义与行为救援相关联的PIN签名。因此,我们建议:(1)定义正常
信息流通过一个由自闭症样基因的蛋白质产物组成的PIN;(2)定义如何
在自闭症小鼠模型中,信息流被中断,目的是充分理解系统
设计有针对性的药物治疗和(3)定义PIN如何对纠正行为的药物作出反应,
可以作为设计PIN修饰治疗以恢复正常突触功能的模板。
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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Stephen Edward Paucha Smith其他文献
Stephen Edward Paucha Smith的其他文献
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{{ truncateString('Stephen Edward Paucha Smith', 18)}}的其他基金
Quantitative protein network profiling to improve CAR design and efficacy
定量蛋白质网络分析以改进 CAR 设计和功效
- 批准号:
10374037 - 财政年份:2020
- 资助金额:
$ 54.53万 - 项目类别:
Quantitative protein network profiling to improve CAR design and efficacy
定量蛋白质网络分析以改进 CAR 设计和功效
- 批准号:
10578701 - 财政年份:2020
- 资助金额:
$ 54.53万 - 项目类别:
Subtyping the autisms using individualized protein network analysis
使用个体化蛋白质网络分析对自闭症进行亚型分类
- 批准号:
10212205 - 财政年份:2020
- 资助金额:
$ 54.53万 - 项目类别:
Purification of cell-type specific synaptic material using virally-expressed tags
使用病毒表达标签纯化细胞类型特异性突触物质
- 批准号:
9980828 - 财政年份:2019
- 资助金额:
$ 54.53万 - 项目类别:
Protein Interaction Network Analysis to Test the Synaptic Hypothesis of Autism
蛋白质相互作用网络分析检验自闭症突触假说
- 批准号:
8616138 - 财政年份:2014
- 资助金额:
$ 54.53万 - 项目类别:
Characterization of Autism Susceptibility Genes on Chromosome 15q11-13
染色体 15q11-13 上自闭症易感基因的特征
- 批准号:
8145607 - 财政年份:2010
- 资助金额:
$ 54.53万 - 项目类别:
Characterization of Autism Susceptibility Genes on Chromosome 15q11-13
染色体 15q11-13 上自闭症易感基因的特征
- 批准号:
7912550 - 财政年份:2010
- 资助金额:
$ 54.53万 - 项目类别:
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