Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution
单细胞分辨率下 TBI 的时空分子底物
基本信息
- 批准号:10200171
- 负责人:
- 金额:$ 57.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAffectAnxietyAtlasesBehaviorBiological MarkersBrainBrain ConcussionBrain regionCell CommunicationCellsCellular Metabolic ProcessChronicCognitiveCommunitiesComplexComputer ModelsDataDimensionsDiseaseDoseEmotionalEnergy MetabolismEventFluorescent in Situ HybridizationFunctional disorderGene Expression RegulationGenesGenomicsGoalsHeterogeneityHippocampus (Brain)In SituIndividualInflammationInjuryInterventionKnowledgeLearningMapsMeasurementMemoryMental DepressionMetabolicMetabolic PathwayMetabolismMitochondriaModelingModernizationMolecularMusNeuronal PlasticityPathogenesisPathogenicityPathologicPathologyPathway interactionsPatternPeptidesPharmacodynamicsPhasePopulationPost-Traumatic Stress DisordersRegulationResolutionResourcesRoleSiteSocial BehaviorSportsSynaptic plasticitySystems BiologyTechnologyTestingTherapeuticTimeTraumatic Brain InjuryValidationYangbrain cellcell typechronic traumatic encephalopathycognitive processemotional behaviorfrontal lobehigh throughput technologyhumanininnovationinsightmild traumatic brain injurymultidisciplinarynervous system disordernetwork modelsneuropathologyneurotransmissionnovelnovel therapeutic interventionpreventresponsesingle cell technologysingle-cell RNA sequencingspatiotemporaltranscriptometranslational medicinetreatment effect
项目摘要
Abstract
Traumatic brain injury (TBI) has a complex neuropathology involving progressive alterations in brain centers
that process cognitive and emotional behaviors and consist of heterogeneous cell populations. The complex
spatiotemporal cell and molecular circuits underlying progressive TBI pathologies that can evolve into other
disorders such as chronic traumatic encephalopathy and posttraumatic stress disorder remain to be
understood. A comprehensive understanding of the molecular mechanisms underlying the complexity of TBI
has been hindered by the lack of effective approaches to examine molecular events in individual brain cells
that drive the overall pathology. We recently conducted a single cell resolution study of the hippocampus at the
acute phase (24hr) of TBI using single cell RNA sequencing (scRNAseq) and revealed cell-type specific
pathways and regulators of TBI. In particular, we found that depression of cell metabolism to be a key
pathogenic component in the hippocampus at the acute phase of TBI. This finding suggests that tracking
metabolic state of cells can be used to address key knowledge gaps on the spatial and time dependent
progression of key pathologic drivers of TBI. Here we propose to test the hypothesis that cell metabolic
regulators determine dynamic and spatial pathogenic pathways of TBI by harnessing the power of modern
high-throughput technologies. We propose a highly integrative team approach to profit from recent advances in
single cell RNA sequencing (scRNAseq) and multiplexed error robust fluorescent in situ hybridization
(MERFISH) along with advanced gene-gene and cell-cell network modeling to inform on targets for intervention
at specific time points or brain sites, a fundamental unsolved question in the TBI field. In Aim 1, we propose to
utilize a unique combination of scRNAseq, MERFISH, and network modeling approaches to assess and
validate the spatial and temporal vulnerability of each cell type to TBI in multiple brain regions at multiple time
points in a data-driven, unbiased manner, which can inform us about hidden regulators of TBI pathogenesis.
We will focus on the spatial and temporal changes in cellular metabolic pathways during TBI progression. Our
preliminary results support that mt-Rnr2, encoding a mitochondrial peptide humanin and involved in cell
metabolism, is a major site- and time-dependent driver of TBI. In Aim 2, we will functionally assess whether
modulating mt-Rnr2 (humanin) has therapeutic potential to mitigate TBI pathology and prevent progression.
We will also explore the cell-type specific mechanisms, especially the role of metabolism, underlying the
actions of humanin. The overall goal of the proposal is to elaborate on an innovative strategy that can offer a
comprehensive mechanistic understanding of the spatiotemporal cell substrates of TBI pathology and uncover
novel targets and mechanisms to redirect the courses of TBI to overcome subsequent neurological disorders.
摘要
创伤性脑损伤具有复杂的神经病理改变,涉及大脑中心的进行性改变。
它处理认知和情感行为,并由不同的细胞群组成。情结
在进行性脑损伤病理基础上的时空细胞和分子电路可以演变为
慢性创伤性脑病和创伤后应激障碍等疾病仍有待于
明白了。全面了解脑外伤复杂性的分子机制
由于缺乏有效的方法来检查单个脑细胞中的分子事件,这一点受到了阻碍
这推动了整个病理过程。我们最近对海马体进行了一项单细胞分辨率研究
应用单细胞RNA测序(ScRNAseq)和揭示细胞类型特异性的脑损伤急性期(24小时)
创伤性脑损伤的信号转导途径和调节因子。特别是,我们发现抑制细胞新陈代谢是一个关键
脑损伤急性期海马区的致病成分。这一发现表明,追踪
细胞的代谢状态可以用来解决空间和时间依赖的关键知识差距
脑外伤的关键病理驱动因素的研究进展。在这里,我们建议检验细胞代谢的假设
调节器通过利用现代的力量来确定脑损伤的动态和空间致病途径
高通量技术。我们提出了一个高度整合的团队方法,以从以下方面的最新进展中获利
单细胞RNA测序(ScRNAseq)和多重错误稳健荧光原位杂交
(MerFish)以及先进的基因-基因和细胞-细胞网络建模,以告知干预目标
在特定的时间点或大脑部位,这是脑损伤领域一个基本尚未解决的问题。在目标1中,我们建议
利用scRNAseq、MerFish和网络建模方法的独特组合来评估和
验证每种细胞类型在多个时间段的多个脑区对脑损伤的时空易损性
以数据驱动、不偏不倚的方式点位,这可以让我们了解脑外伤发病机制的隐藏调控因素。
我们将关注脑外伤进展过程中细胞代谢途径的空间和时间变化。我们的
初步结果支持mt-Rnr2,编码一种线粒体多肽Human in,并参与细胞
代谢,是脑损伤的主要部位和时间依赖的驱动因素。在目标2中,我们将从功能上评估
调节mt-Rnr2(人素)具有减轻脑损伤病理和防止进展的治疗潜力。
我们还将探索细胞类型的特定机制,特别是新陈代谢的作用,潜在的
人类的行为。该提案的总体目标是详细阐述一种创新战略,该战略可以提供
全面理解脑外伤病理和发现的时空细胞底物
新的靶点和机制,以改变脑损伤的进程,以克服随后的神经障碍。
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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Fernando Gomez-Pinilla其他文献
Fernando Gomez-Pinilla的其他文献
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{{ truncateString('Fernando Gomez-Pinilla', 18)}}的其他基金
Precision Medicine Approach: Using genomic information to guide TBI treatment
精准医学方法:利用基因组信息指导 TBI 治疗
- 批准号:
10303991 - 财政年份:2021
- 资助金额:
$ 57.62万 - 项目类别:
Precision Medicine Approach: Using genomic information to guide TBI treatment
精准医学方法:利用基因组信息指导 TBI 治疗
- 批准号:
10548225 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Precision Medicine Approach: Using genomic information to guide TBI treatment
精准医学方法:利用基因组信息指导 TBI 治疗
- 批准号:
9916553 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution
单细胞分辨率下 TBI 的时空分子底物
- 批准号:
10386933 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Precision Medicine Approach: Using genomic information to guide TBI treatment
精准医学方法:利用基因组信息指导 TBI 治疗
- 批准号:
10084332 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Strategy to Potentiate Rehabilitation after TBI
加强 TBI 后康复的策略
- 批准号:
10308503 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Precision Medicine Approach: Using genomic information to guide TBI treatment
精准医学方法:利用基因组信息指导 TBI 治疗
- 批准号:
10556740 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Strategy to Potentiate Rehabilitation after TBI
加强 TBI 后康复的策略
- 批准号:
10533276 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Precision Medicine Approach: Using genomic information to guide TBI treatment
精准医学方法:利用基因组信息指导 TBI 治疗
- 批准号:
10328921 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution
单细胞分辨率 TBI 的时空分子底物
- 批准号:
10606498 - 财政年份:2020
- 资助金额:
$ 57.62万 - 项目类别:
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