Spatial and Single Cell Transcriptomics Approach to Understand Neuron-Oligodendrocyte Communication in Human Synaptic Development
了解人类突触发育中神经元-少突胶质细胞通讯的空间和单细胞转录组学方法
基本信息
- 批准号:10646970
- 负责人:
- 金额:$ 20.93万
- 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:2023-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAction PotentialsAdherent CultureAntibodiesArchitectureAreaBar CodesBiological AssayBiologyBrainCell Culture TechniquesCell MaturationCellsCentral Nervous SystemCerebrumCoculture TechniquesCommunicationCommunitiesComplementary DNADataData SetDevelopmentDiphtheria ToxinDiseaseElectrophysiology (science)FormulationFoundationsFundingFutureGenerationsGenesGrantHistologicHistologyHumanIn VitroInstitutional Review BoardsIntellectual functioning disabilityKnowledgeLive BirthMapsMeasurementMediatingMethodsMolecularMorphologyMultiple SclerosisMusMyelinNamesNervous System PhysiologyNeurogliaNeurologic DysfunctionsNeuronsOligodendrogliaOntologyPathologyPatientsPregnancyPremature BirthPremature InfantProtocols documentationRegulationReportingResolutionRodentRodent ModelRoleSecureSignal TransductionSliceSlideSourceSynapsesSystemTHBS2 geneTestingTissue DonorsTissuesUniversitiesVentricularWNT5A geneWNT7A genebrain tissueclinical translationdrug candidatedrug testingeffective therapyexperimental studyfetus cellgenetic signaturehuman tissueleukodystrophyneuron developmentneuropsychiatric disordernovelnovel therapeuticsoligodendrocyte precursorpostsynapticprecursor cellpresynapticsingle-cell RNA sequencingspatial relationshipsynaptic functiontranscriptomic profilingtranscriptomicstransmission processwhite matter injury
项目摘要
ABSTRACT
Oligodendrocytes are the myelinating glia cells of the central nervous system allowing coordinated conduction
of action potentials among neurons, thus imperative for proper neurological functions. The vast majority of our
knowledge in oligodendrocytes is derived from rodent models. Perhaps for that reason, clinical translation of our
knowledge has been limited, leaving many disorders without treatment. In order to understand the fundamental
human oligodendrocyte development, pathology, and ultimately to discover drug candidates with higher
confidence, therefore, it is necessary to develop protocols in human-based platform. Single-cell RNA sequencing
comparing mouse and human oligodendrocyte precursor cells (OPCs) revealed a compelling unique sub-
population in human OPCs that does not seem to exist in mouse OPCs. More importantly, gene ontology analysis
of this sub-population identified highly expressed signature genes associated with synaptic development,
organization, and transmission, suggesting neuron-oligodendrocyte communication during neuronal
development. To our knowledge, there are no reports suggested a direct synaptic control by OPCs. Based on
these observations, we hypothesize that a sub-population of human OPCs regulates synaptic development. This
proposal intends to establish concrete evidence for human-specific OPC sub-population through two pilot
experiments to prepare for a future external funding focusing on understanding the molecular mechanisms of
human synaptic development controlled by OPCs. First, to define temporal and spatial interaction between
human specific OPC sub-population and neurons, we will generate spatial transcriptomic profiling of developing
human brain spanning gestational week 10 to 24, when dynamic synaptic development as well as OPC
maturation occur. Spatial transcriptomics uses an intact tissue section mounted on a slide that is coated with
arrays of barcoded RT primers to create spatially barcoded cDNA, allowing us to obtain transcriptomic data from
the entire tissue retaining spatial information. These data will reveal where the OPC sub-population exists in
developing brains and what type(s) of neighboring neurons they are interacting with. Second, we will begin to
test the function of human specific OPC sub-population using quantitative electrophysiology in a co-culture and
slice culture formats that we have optimized. Once achieved, these studies will lay the foundation to study a
novel function of human OPC sub-population. Generated transcriptomic datasets will allow us to formulate
testable hypotheses for future external grants. In a larger perspective, discovery of a new mechanism in synaptic
control may lead to a re-formulation of the pathomechanisms in diseases with suspected involvement of
oligodendrocytes, such as intellectual disabilities and neuropsychiatric disorders.
抽象的
少突胶质细胞是中枢神经系统的髓鞘神经胶质细胞,可协调传导
神经元之间的动作电位,因此对于正常的神经功能至关重要。我们的绝大多数
少突胶质细胞的知识源自啮齿动物模型。也许正是出于这个原因,我们的临床翻译
知识有限,导致许多疾病得不到治疗。为了理解基本原理
人类少突胶质细胞的发育、病理学,并最终发现具有更高性能的候选药物
因此,有必要在人性化的平台上开发协议。单细胞 RNA 测序
比较小鼠和人类少突胶质细胞前体细胞 (OPC) 揭示了一种令人信服的独特亚
人类 OPC 中似乎不存在小鼠 OPC 中的群体。更重要的是,基因本体分析
该亚群中鉴定出与突触发育相关的高表达特征基因,
组织和传输,表明神经元-少突胶质细胞在神经元过程中进行通讯
发展。据我们所知,没有报告表明 OPC 可以直接控制突触。基于
根据这些观察结果,我们假设人类 OPC 的一个亚群调节突触发育。这
该提案旨在通过两个试点为人类特定的 OPC 亚群建立具体证据
为未来的外部资助做准备的实验,重点是了解其分子机制
人类突触发育受 OPC 控制。首先,定义时间和空间之间的相互作用
人类特定的 OPC 亚群和神经元,我们将生成发育中的空间转录组分析
人脑跨越妊娠第 10 周至第 24 周,此时动态突触发育以及 OPC
发生成熟。空间转录组学使用安装在载玻片上的完整组织切片,载玻片涂有
带条形码的 RT 引物阵列来创建带空间条形码的 cDNA,使我们能够从
整个组织保留空间信息。这些数据将揭示 OPC 亚群存在于何处
发育中的大脑以及它们与哪些类型的邻近神经元相互作用。其次,我们将开始
使用定量电生理学在共培养物中测试人类特定 OPC 亚群的功能
我们已经优化的切片培养格式。一旦实现,这些研究将为研究奠定基础
人类 OPC 亚群的新功能。生成的转录组数据集将使我们能够制定
未来外部资助的可检验假设。从更大的角度来看,突触新机制的发现
控制可能会导致怀疑涉及以下疾病的病理机制的重新制定
少突胶质细胞,例如智力障碍和神经精神疾病。
项目成果
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