Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
基本信息
- 批准号:9069107
- 负责人:
- 金额:$ 24.9万
- 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:2014-06-05 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:Advisory CommitteesAlternative SplicingAreaAwardBindingBinding SitesBioinformaticsBrainComplementCouplingDNA Sequence AlterationDataData SetDefectDevelopmentExcitatory SynapseGene ExpressionGeneticGlutamate ReceptorGoalsHigh-Throughput Nucleotide SequencingHumanImmunoprecipitationIn VitroKnockout MiceKnowledgeLeadLightMammalian CellMediatingMental disordersMentorsMessenger RNAMicroRNAsMissionMolecular BiologyMorphologyNervous system structureNeuronsNeurosciencesOutcomeOutputPathogenesisPathway interactionsPhasePhysiologicalPositioning AttributeProteinsPublic HealthQuality ControlRNARNA BindingRNA ProcessingRegulationRegulatory PathwayResearchResearch Project GrantsRodentRoleScaffolding ProteinSpecificitySynapsesTechnical ExpertiseTechniquesTerminator CodonTestingTherapeutic InterventionTrainingTranscriptTranscriptional RegulationTranslationsVertebral columnYangbasecareer developmentcollaborative environmentcrosslinkcrosslinking and immunoprecipitation sequencingdensitydisabilityexperiencegenome-widegenome-wide analysisin vivomRNA DecaymRNA Transcript Degradationmouse modelneurodevelopmentneuron developmentneuropsychiatric disorderneuropsychiatrynovelpostsynapticpostsynaptic density proteinprematureresearch studyskillstooltranscriptome sequencing
项目摘要
PROJECT SUMMARY
Defects in the nonsense-mediated mRNA decay (NMD) pathway have recently been implicated in multiple
neuropsychiatric diseases. However, this pathway has not been well studied in the brain and disruption of
NMD in neurons has not been characterized. We recently discovered a novel regulatory role of the NMD
pathway in the nervous system. Through coupling to alternative splicing regulation, NMD controls the
expression level of postsynaptic density protein 95 (PSD-95), an essential scaffold protein of the excitatory
PSD. This mechanism of regulation is similar to the output of transcriptional control, but it is unclear what other
natural neuronal transcripts are regulated by NMD. My long term goal is to understand the role of NMD-
mediated regulation in the nervous system, and how errors in NMD can lead to neuropsychiatric disorders. The
objective of this proposal is to characterize fundamental developmental defects resulting from deficiencies in
the NMD pathway and systematically identify physiological NMD substrates in rodent neurons. I have already
generated an NMD deficient mouse model and developed various techniques for this proposal. Guided by
strong preliminary data, I will pursue two specific aims: 1) Genome-wide identification of NMD targets important
for neuronal development; 2) Characterize the physiological requirement for the NMD pathway during
development. Based on preliminary data, two important aspects of synapse development, spine morphology
and synaptic expression of glutamate receptors, will be examined thoroughly in NMD deficient neurons both in
vivo and in vitro. Identification of natural NMD substrates in neurons will shed light on how frequently NMD is
used as an active regulatory pathway of gene expression rather than a passive quality-control mechanism.
Knowledge about the genetic roles and specific targets of NMD in brain provides a novel perspective for
understanding the pathogenesis of various neuropsychiatric diseases and may help point to the common
targets/pathways for therapeutic intervention.
I have a background in both cellular neuroscience and RNA molecular biology. I am in a unique position to
contribute to the proposed research area. To further prepare myself for my long-term research goal, I plan to
seek training that will complement my existing technical skills and further develop my professional skills. UCLA
has a highly collaborative environment ideal to this project and for me to achieve these goals. My mentor, Dr.
Douglas Black, is one of the world-class experts in alternative splicing regulation. I also have an advisory
committee that consists of Dr. Kelsey Martin, Dr. Tom O'Dell, and Dr. William Yang and provide
complementary inputs on neuroscience. My mentor team has a detailed plan to facilitate my research progress
and scientific career development. In summary, my educational and research experience together with a
strong and supportive mentoring team make me an ideal candidate for this research project and the K99/R00
award.
项目概要
无义介导的 mRNA 衰减 (NMD) 途径的缺陷最近与多种
神经精神疾病。然而,这一途径尚未在大脑中得到充分研究,并且对
神经元中的 NMD 尚未得到表征。我们最近发现了 NMD 的一种新的监管作用
神经系统中的通路。通过耦合选择性剪接调节,NMD 控制
突触后密度蛋白 95 (PSD-95) 的表达水平,PSD-95 是兴奋性神经细胞的重要支架蛋白
PSD。这种调节机制与转录控制的输出类似,但尚不清楚还有哪些其他机制
天然神经元转录本受 NMD 调节。我的长期目标是了解 NMD 的作用-
神经系统介导的调节,以及 NMD 错误如何导致神经精神疾病。这
该提案的目的是描述由于以下方面的缺陷而导致的基本发育缺陷的特征:
NMD 通路并系统地识别啮齿动物神经元中的生理 NMD 底物。我已经
生成了 NMD 缺陷小鼠模型并为此提案开发了各种技术。指导者
有了强有力的初步数据,我将追求两个具体目标:1)全基因组识别 NMD 目标很重要
用于神经元发育; 2) 表征 NMD 途径的生理需求
发展。根据初步数据,突触发育的两个重要方面,脊柱形态
和谷氨酸受体的突触表达,将在 NMD 缺陷神经元中进行彻底检查
体内和体外。神经元中天然 NMD 底物的鉴定将揭示 NMD 发生的频率
用作基因表达的主动调控途径,而不是被动的质量控制机制。
关于 NMD 在大脑中的遗传作用和特定靶标的知识为
了解各种神经精神疾病的发病机制,可能有助于指出常见的疾病
治疗干预的目标/途径。
我拥有细胞神经科学和 RNA 分子生物学的背景。我处于一个独特的位置
为拟议的研究领域做出贡献。为了进一步为我的长期研究目标做好准备,我计划
寻求培训来补充我现有的技术技能并进一步发展我的专业技能。加州大学洛杉矶分校
有一个高度协作的环境,非常适合这个项目和我实现这些目标。我的导师,博士。
道格拉斯·布莱克(Douglas Black)是选择性剪接调控领域的世界级专家之一。我也有咨询
由 Kelsey Martin 博士、Tom O'Dell 博士和 William Yang 博士组成的委员会,并提供
神经科学方面的补充投入。我的导师团队有一个详细的计划来促进我的研究进展
和科学的职业发展。总之,我的教育和研究经历以及
强大且支持性的指导团队使我成为该研究项目和 K99/R00 的理想候选人
奖。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Alternative splicing and nonsense-mediated mRNA decay enforce neural specific gene expression.
- DOI:10.1016/j.ijdevneu.2016.03.003
- 发表时间:2016-12
- 期刊:
- 影响因子:0
- 作者:Zheng S
- 通讯作者:Zheng S
Alternative pre-mRNA splicing in neurons: growing up and extending its reach.
- DOI:10.1016/j.tig.2013.04.003
- 发表时间:2013-08
- 期刊:
- 影响因子:11.4
- 作者:Zheng, Sika;Black, Douglas L.
- 通讯作者:Black, Douglas L.
A Cell-Based High-Throughput Method for Identifying Modulators of Alternative Splicing.
一种基于细胞的高通量方法,用于识别选择性剪接的调节剂。
- DOI:10.1007/978-1-4939-7204-3_16
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Zheng,Sika
- 通讯作者:Zheng,Sika
IRAS: High-Throughput Identification of Novel Alternative Splicing Regulators.
IRAS:新型选择性剪接调节剂的高通量鉴定。
- DOI:10.1016/bs.mie.2016.02.024
- 发表时间:2016
- 期刊:
- 影响因子:0
- 作者:Zheng,S
- 通讯作者:Zheng,S
Inhibition of nonsense-mediated RNA decay by ER stress.
- DOI:10.1261/rna.058040.116
- 发表时间:2017-03
- 期刊:
- 影响因子:0
- 作者:Li Z;Vuong JK;Zhang M;Stork C;Zheng S
- 通讯作者:Zheng S
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{{ truncateString('Sika Zheng', 18)}}的其他基金
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10572698 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10755022 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10356466 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10532374 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
The regulation and function of neuron-specific alternative splicing
神经元特异性选择性剪接的调控和功能
- 批准号:
10063921 - 财政年份:2017
- 资助金额:
$ 24.9万 - 项目类别:
The Regulation and Function of Neuron-Specific Alternative Splicing
神经元特异性选择性剪接的调控和功能
- 批准号:
10318594 - 财政年份:2017
- 资助金额:
$ 24.9万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8834110 - 财政年份:2014
- 资助金额:
$ 24.9万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8878168 - 财政年份:2014
- 资助金额:
$ 24.9万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8507514 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8641419 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
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