Identifying mechanisms ofsynapse maturation at neuronal subtype resolution
识别神经元亚型分辨率下突触成熟的机制
基本信息
- 批准号:10739241
- 负责人:
- 金额:$ 9.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ARHGEF5 geneAcuteAdaptive BehaviorsAffectAwardBehaviorBiologyBrainBrain DiseasesCellsCerebral cortexCharacteristicsChemical SynapseChromatinCritical PathwaysDNA Sequence AlterationDataDevelopmentDiseaseEpigenetic ProcessExhibitsFoundationsFunctional disorderFutureGene ExpressionGene Expression ProfileGeneticGenetic TranscriptionGenetic studyGenomicsGlutamatesGoalsHeterogeneityHumanIndividualInterneuronsKnowledgeLabelLearningLinkLong-Term EffectsMachine LearningMaintenanceMediatingMental disordersMentorsMethodsMolecularMusMutationNeuronsPathway interactionsPatientsPhasePlayProcessPropertyProteinsProteomeProteomicsRegulator GenesResearchResearch Project GrantsResolutionRisk FactorsRodent ModelRoleSolidSpecificitySynapsesSynaptic TransmissionSynaptic plasticityTechniquesTestingTrainingTranscriptional Regulationautism spectrum disordercareercell typecritical perioddensitydesigner receptors exclusively activated by designer drugsdevelopmental neurobiologyexperiencegene regulatory networkin vivoinsightknock-downmachine learning methodmultiple omicsneural circuitnovelpostsynapticpostsynaptic density proteinprogramsprotein complexsingle-cell RNA sequencingskillssynaptogenesistargeted treatmenttemporal measurementtool
项目摘要
Project Summary/Abstract
The human brain function relies on the formation and maintenance of precise neural circuits among more than
100 subtypes of neurons. These circuits are mediated by synapses, the characteristics of which vary depending
on neuronal subtype. Synaptic dysfunction plays a critical role in most, if not all, human brain disorders. Thus,
understanding synaptic diversity and its developmental origin are crucial for us to understand how the brain
functions and how it goes awry in mental disorders. During brain development, synapses undergo profound
changes to become mature and fully functional. Maturation of glutamatergic synapses involves changes in the
postsynaptic density (PSD), a highly sophisticated protein complex composed of >1,000 proteins. However, the
compositional changes of the PSD in development were not well characterized. My preliminary data revealed
the temporal dynamics of >1,000 PSD proteins during cerebral cortex development, providing initial insight into
mechanisms of synapse maturation. Moreover, integrative analysis of the developing PSD proteome and single-
cell RNA-seq data suggested that different neuronal subtypes undergo divergent synapse maturation processes.
However, we know little about the compositional diversity of neuronal subtype-specific synapses or the different
maturation processes they go through. In addition, synapse maturation, diversity, and specificity can be
controlled by transcription, but the underlying gene regulatory programs remain elusive. This information is
particularly relevant to mental disorders like autism spectrum disorder, in which genetic mutations converge on
transcription regulation and synaptic transmission. Thus, the specific aims of this project first seek to uncover
the compositional diversity of neuronal subtype-specific synapses in the developing cerebral cortex using a novel
chemogenetic method (Aim 1, K99 phase). The second aim is to decode the disease-relevant gene regulatory
mechanisms that generate this diversity by applying single-cell genomics and machine learning approaches (Aim
2, K99 phase). Finally, using the training, tools, and preliminary data from the K99 phase of my proposal, I will
launch an independent research project that focuses on investigating the effects of neuronal activity on synapse
maturation and plasticity at neuronal subtype resolution (R00 phase). Results from these studies will provide
insights into synapse diversity, its regulatory mechanisms, and its dysregulation in autism. My long-term goal is
to study the functional importance of synapse diversity on neural circuits and behaviors and develop targeted
therapies to alleviate synaptic dysfunction in mental disorders in patients. Additional training obtained during this
award in developmental neurobiology (with Dr. Arnold Kriegstein), synaptic biology (with Dr. Robert Edwards),
chemogenetics (with Dr. Alice Ting), and advanced machine learning (with Dr. Jingjing Li), combined with my
previous experience in rodent models, proteomics, and single-cell genomics will provide me with a solid
foundation for an independent research career to achieve my goal.
项目总结/摘要
人类大脑的功能依赖于在超过1000个神经元中形成和维持精确的神经回路。
神经元的100种亚型这些回路是由突触介导的,突触的特性根据
神经元亚型突触功能障碍在大多数(如果不是全部)人类大脑疾病中起着关键作用。因此,在本发明中,
了解突触的多样性及其发育起源对于我们理解大脑如何
以及它在精神疾病中的作用。在大脑发育过程中,
变化变得成熟和功能齐全。神经元突触的成熟涉及神经元内
突触后致密物(PSD)是由超过1,000种蛋白质组成的高度复杂的蛋白质复合物。但
没有很好地表征发展中PSD的组成变化。我的初步数据显示
大脑皮层发育过程中> 1,000 PSD蛋白的时间动态,提供了对
突触成熟的机制。此外,综合分析发展PSD蛋白质组和单一的,
细胞RNA-seq数据表明,不同的神经元亚型经历不同的突触成熟过程。
然而,我们对神经元亚型特异性突触的组成多样性或不同的突触类型知之甚少。
他们经历的成熟过程。此外,突触的成熟、多样性和特异性也可能是
基因调控是由转录控制的,但潜在的基因调控程序仍然难以捉摸。该信息
特别是与自闭症谱系障碍等精神障碍有关,其中基因突变集中在
转录调节和突触传递。因此,本项目的具体目标首先是揭示
在发育中的大脑皮层神经元亚型特异性突触的组成多样性,使用一种新的
化学遗传学方法(Aim 1,K99阶段)。第二个目标是解码疾病相关的基因调控,
通过应用单细胞基因组学和机器学习方法产生这种多样性的机制(Aim
2、K99相)。最后,利用我的建议书K99阶段的培训、工具和初步数据,我将
启动一个独立的研究项目,重点研究神经元活动对突触的影响。
在神经元亚型分辨(R 00期)的成熟和可塑性。这些研究的结果将提供
深入了解突触多样性,其调节机制,以及自闭症的失调。我的长期目标是
研究突触多样性对神经回路和行为的功能重要性,
缓解精神障碍患者的突触功能障碍的疗法。在此期间获得的额外培训
发育神经生物学(与Arnold Kriegstein博士合作),突触生物学(与Robert Edwards博士合作),
化学遗传学(与Alice Ting博士)和先进的机器学习(与Jingjing Li博士),结合我的
以前在啮齿动物模型,蛋白质组学和单细胞基因组学方面的经验将为我提供坚实的
独立研究生涯的基础,以实现我的目标。
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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Li Wang其他文献
Numerical Algorithms of the Discrete Coupled Algebraic Riccati Equation Arising in Optimal Control Systems
最优控制系统中离散耦合代数Riccati方程的数值算法
- DOI:
10.1155/2020/1841582 - 发表时间:
2020-08 - 期刊:
- 影响因子:0
- 作者:
Li Wang - 通讯作者:
Li Wang
Li Wang的其他文献
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{{ truncateString('Li Wang', 18)}}的其他基金
Volume-based Analysis of 6-month Infant Brain MRI for Autism Biomarker Identification and Early Diagnosis
用于自闭症生物标志物识别和早期诊断的 6 个月婴儿脑部 MRI 体积分析
- 批准号:
9243470 - 财政年份:2017
- 资助金额:
$ 9.1万 - 项目类别:
Do Access Barriers to Autism Care Persist Despite Autism Insurance Mandate?
尽管有自闭症保险规定,获得自闭症护理的障碍是否仍然存在?
- 批准号:
8544496 - 财政年份:2012
- 资助金额:
$ 9.1万 - 项目类别:
Do Access Barriers to Autism Care Persist Despite Autism Insurance Mandate?
尽管有自闭症保险规定,获得自闭症护理的障碍是否仍然存在?
- 批准号:
8702235 - 财政年份:2012
- 资助金额:
$ 9.1万 - 项目类别:
Do Access Barriers to Autism Care Persist Despite Autism Insurance Mandate?
尽管有自闭症保险规定,获得自闭症护理的障碍是否仍然存在?
- 批准号:
8439498 - 财政年份:2012
- 资助金额:
$ 9.1万 - 项目类别:
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