Regulation of Synapse Formation and Function by Neurexin-1 Proteolysis
Neurexin-1 蛋白水解调节突触形成和功能
基本信息
- 批准号:9110352
- 负责人:
- 金额:$ 5.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-16 至 2017-08-15
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAdultAffectBehaviorBindingBiological ProcessCell Adhesion MoleculesCellsChronicComplexConsensusDataDetectionDevelopmentElectrophysiology (science)EnzymesEtiologyFosteringFrequenciesGene DeletionGenesGeneticGenetic VariationGlutamatesGoalsHealthHippocampus (Brain)HumanIon ChannelKnock-inKnock-in MouseKnockout MiceKnowledgeLigandsMeasuresMediatingMetalloproteasesMolecularMolecular BiologyMorphologyMusNeurobiologyNeurodevelopmental DisorderNeuronsOrganellesPathogenesisPhysiologicalPlayProbabilityProcessProteolysisProteolytic ProcessingRegulationResearchResistanceRoleSchizophreniaSeriesSignal TransductionSiteSite-Directed MutagenesisStructureSynapsesSynaptic TransmissionTestingThrombinTrainingWhole-Cell Recordingsautism spectrum disordercareerdensityextracellulargene functionimprovedinhibitor/antagonistinsightmouse modelmutantneurotransmitter releasenew therapeutic targetnovelpatch clamppostsynapticpresynapticresearch studysynaptic functionsynaptogenesis
项目摘要
DESCRIPTION (provided by applicant): The formation, maturation, and function of synapses requires the exquisite coordination of transynaptic adhesion complexes, enabling the concentration and control of pre- and postsynaptic signaling machinery. In particular, the association of presynaptic neurexins (Nrxns) with their postsynaptic ligands (e.g. neuroligins, LRRTMs, etc.), mediates several aspects of synaptic function, such as synaptic transmission and the assembly of functional postsynaptic sites. A growing body of genetic evidence implicates heterozygous deletions of the gene encoding Nrxn-1 in the pathoetiology of idiopathic autism spectrum disorders and schizophrenia. Still very little is known regarding the function and regulation of Nrxn-1 at developing and adult synapses, an understanding of which may improve our knowledge of neurodevelopmental disorders and reveal novel pharmacological targets. I present here preliminary data that validates the use of two new mouse models for studying Nrxn-1, including a Nrxn-1-HA knockin mouse which will allow improved detection of endogenous Nrxn-1, as well as a Nrxn-1?/? conditional knockout mouse (cKO) mouse for functional studies. Using the Nrxn-1-HA knockin, I further show that synaptic activity influences the processing of Nrxn-1 in a metalloproteinase-dependent fashion, which may represent an important regulatory mechanism of Nrxn- containing adhesion complexes. In order to better understand the basic function and regulation of Nrxn-1 at synapses, I propose to identify the specific metalloproteinase and cleavage site responsible for activity- dependent Nrxn-1 processing. Then I will determine, in parallel, the basic function of Nrxn-1 in regulating the formation and physiological function of hippocampal synapses. Finally, through a series of rescue experiments achieved through lentiviral re-expression of wild-type, cleavage-resistant, and cleavage-inducible Nrxn-1� in Nrxn-1�/� cKO neurons, I will assess the role of Nrxn-1 processing in its normal function. It is anticipated that the proposed research will provide fundamental insight into how Nrxn-1 deletions give rise to human neurodevelopmental disorders and will offer the first functional analysis of extracellular proteolysis as a regulatory mechanism
of neurexin-containing adhesion complexes.
描述(申请人提供):突触的形成、成熟和功能需要跨突触粘附复合物的精细协调,从而实现突触前和突触后信号机制的集中和控制。特别是,突触前神经素(Nrxns)与其突触后配体(如神经素、lrrtm等)的关联介导了突触功能的几个方面,如突触传递和功能性突触后位点的组装。越来越多的遗传证据表明,编码Nrxn-1的基因杂合缺失与特发性自闭症谱系障碍和精神分裂症的病理机制有关。关于Nrxn-1在发育和成年突触中的功能和调控,我们所知甚少,对其的理解可能会提高我们对神经发育障碍的认识,并揭示新的药理靶点。我在这里提供了初步数据,验证了使用两种新的小鼠模型来研究Nrxn-1,包括Nrxn-1- ha敲入小鼠,它可以改进内源性Nrxn-1的检测,以及Nrxn-1?/?条件敲除小鼠(cKO)小鼠用于功能研究。利用Nrxn-1- ha敲入蛋白,我进一步证明突触活性以金属蛋白酶依赖的方式影响Nrxn-1的加工,这可能代表了Nrxn-含粘附复合物的重要调节机制。为了更好地了解Nrxn-1在突触中的基本功能和调控,我建议确定负责活性依赖性Nrxn-1加工的特定金属蛋白酶和切割位点。然后,我将同时确定Nrxn-1在调节海马突触形成和生理功能方面的基本功能。最后,通过慢病毒在Nrxn-1 / cKO神经元中重新表达野生型、抗分裂型和诱导分裂型Nrxn-1的一系列拯救实验,我将评估Nrxn-1加工在其正常功能中的作用。预计这项拟议的研究将为Nrxn-1缺失如何引起人类神经发育障碍提供基本的见解,并将首次提供细胞外蛋白水解作为调节机制的功能分析
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Justin Howard Trotter其他文献
Justin Howard Trotter的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Justin Howard Trotter', 18)}}的其他基金
Molecular Logic Sculpting Cell-Specific Contributions of Neurexin-1 at the Tripartite Synapse
分子逻辑塑造 Neurexin-1 对三联突触的细胞特异性贡献
- 批准号:
10224581 - 财政年份:2021
- 资助金额:
$ 5.61万 - 项目类别:
Molecular Logic Sculpting Cell-Specific Contributions of Neurexin-1 at the Tripartite Synapse
分子逻辑塑造 Neurexin-1 对三联突触的细胞特异性贡献
- 批准号:
10594568 - 财政年份:2021
- 资助金额:
$ 5.61万 - 项目类别:
Molecular Logic Sculpting Cell-Specific Contributions of Neurexin-1 at the Tripartite Synapse
分子逻辑塑造 Neurexin-1 对三联突触的细胞特异性贡献
- 批准号:
10378089 - 财政年份:2021
- 资助金额:
$ 5.61万 - 项目类别:
Regulation of Synapse Formation and Function by Neurexin-1 Proteolysis
Neurexin-1 蛋白水解调节突触形成和功能
- 批准号:
8781325 - 财政年份:2014
- 资助金额:
$ 5.61万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 5.61万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 5.61万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 5.61万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 5.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 5.61万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 5.61万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 5.61万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 5.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 5.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 5.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)