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:8834110
- 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 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:Advisory CommitteesAlternative SplicingAreaAwardBindingBinding SitesBioinformaticsBrainComplementCouplingDataData SetDefectDevelopmentDiseaseEnvironmentExcitatory SynapseGene ExpressionGene MutationGeneticGlutamate ReceptorGoalsHigh-Throughput Nucleotide SequencingHumanImmunoprecipitationIn VitroKnockout MiceKnowledgeLeadLightMammalian CellMediatingMental disordersMentorsMessenger RNAMicroRNAsMissionMolecular BiologyMorphologyNervous system structureNeuronsNeurosciencesOutcomeOutputPathogenesisPathway interactionsPhasePhysiologicalPositioning AttributeProteinsPublic HealthQuality ControlRNARNA BindingRNA ProcessingRegulationRegulatory PathwayResearchResearch Project GrantsRodentRoleScaffolding ProteinSpecificitySynapsesTechniquesTerminator CodonTestingTherapeutic InterventionTrainingTranscriptTranscriptional RegulationTranslationsVertebral columnYangbasecareer developmentcrosslinkdensitydisabilityexperiencegenome wide association studygenome-widein vivomRNA DecaymRNA Transcript Degradationmouse modelneurodevelopmentneuron developmentneuropsychiatrynovelpostsynapticpostsynaptic 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.
项目总结
无义介导的信使核糖核酸衰退(NMD)途径的缺陷最近被认为与多发性
神经精神疾病。然而,这一途径在大脑中还没有得到很好的研究,而且
神经元中的NMD还没有被表征。我们最近发现了NMD的一种新的调节作用
神经系统中的通路。通过耦合到替代剪接调节,NMD控制
兴奋性必需支架蛋白突触后密度蛋白95的表达水平
PSD。这种调控机制类似于转录控制的输出,但还不清楚还有什么其他机制
天然神经元转录本受NMD调控。我的长期目标是了解NMD的作用-
神经系统的中介调节,以及NMD的错误如何导致神经精神障碍。这个
这项建议的目的是描述由以下缺陷引起的基本发育缺陷
NMD途径,并系统地鉴定啮齿动物神经元中的生理性NMD底物。我已经去过了
建立了NMD缺陷的小鼠模型,并为这一提议开发了各种技术。指导原则
强大的初步数据,我将追求两个具体目标:1)在全基因组范围内识别NMD目标
用于神经元发育;2)表征NMD途径在
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缺陷的神经元中进行彻底的检测,
体内和体外。神经元中天然NMD底物的鉴定将有助于了解NMD发生的频率
用作基因表达的主动调节途径,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点的知识为
了解各种神经精神疾病的发病机制,有助于指出常见的
治疗干预的目标/途径。
我有细胞神经科学和RNA分子生物学的背景。我处于一个独特的位置
对拟议的研究领域作出贡献。为了进一步为我的长期研究目标做准备,我计划
寻求培训,以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,对这个项目和我实现这些目标来说都是理想的。我的导师,Dr。
道格拉斯·布莱克是另类剪接监管领域的世界级专家之一。我还有一个忠告
由凯尔西·马丁博士、汤姆·奥戴尔博士和威廉·杨博士组成的委员会,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。总而言之,我的教育和研究经验以及
强大和支持的指导团队使我成为这个研究项目和K99/R00的理想人选
获奖。
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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Sika Zheng的其他文献
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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:
9069107 - 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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