Utilizing Human Brain Organoids to Model the Differential Effects of SCN8A Mutation on Cortex and Hippocampus
利用人脑类器官模拟 SCN8A 突变对皮层和海马的不同影响
基本信息
- 批准号:10624428
- 负责人:
- 金额:$ 23.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAnticonvulsantsArchitectureBiological ModelsBiomedical ResearchBrainBrain regionCalciumCellsChildChildhoodComplexDataDefectDevelopmentDiseaseDrug usageElectrodesElementsEmbryoEpilepsyEtiologyFrequenciesFunctional disorderGenerationsGoalsHippocampusHumanImageImmunohistochemistryImpaired cognitionImpairmentIn VitroIndividualInterneuronsMedicalMemory impairmentMethodologyModelingMorphologyMutationNeural Network SimulationNeurodevelopmental DisorderNeuronsOrganoidsPathogenicityPatientsPatternPhenotypePhysiologicalPlayPluripotent Stem CellsPopulationProsencephalonPublic HealthPublishingRefractoryResearchRett SyndromeRoleSCN8A geneSchool-Age PopulationScientistSeizuresSodium ChannelSortingStructureSubcellular AnatomySyndromeSystemTechniquesTechnologyTestingTherapeuticTherapeutic AgentsTissuesTrainingValidationWorkcalcium indicatorcareercell typechildhood epilepsycomparison controldrug testingeffective therapyepileptic encephalopathiesepileptiformexcitatory neuronextracellulargain of functiongain of function mutationgenetic manipulationgenetic varianthuman diseasehuman embryonic stem cellin vivoinduced pluripotent stem cellinhibitory neuroninsightmemory consolidationmigrationmutantneonatal seizurenervous system disorderneuralneural circuitneural modelneural networkneurodevelopmentneurophysiologynew technologynew therapeutic targetnovelnovel therapeuticsprogramsstem cell biologysynaptogenesistherapeutic targetthree dimensional structuretwo-photonvoltage
项目摘要
Project Summary/Abstract
Epilepsy is a severe and debilitating disease and a significant public health concern. Epilepsy is also a
disease without a medical cure, and a disease where about 1 in 3 patients fails to respond to anti-seizure
medications. In the most severe epilepsy syndromes of childhood, medical control of seizures can be even
more challenging. Novel experimental platforms have the potential to play a critical role in advancing our
understanding and treatment of epilepsy. Brain organoids derived from human embryonic or induced
pluripotent stem cells are one such novel technology that has enormous potential. This is particularly true for
severe childhood epilepsies, as organoids are ideally suited to model early neural development. Organoids are
3D structures that recapitulate complex elements of human brain such as its laminar organization and cell
types seen in all six layers of human cortex. Since they can be human induced-pluripotent stem cell (hiPSC)
derived, an organoid can be produced directly from patient tissue. Recent advances in organoid technology
have resulted in the ability to generate distinct brain region-like organoids such as forebrain cortex and
hippocampus and to make “fusion” structures with integration of inhibitory and excitatory cell types.
In the following proposal I will leverage these advances and build on an organoid platform that I have
recently developed to model brain circuit formation and dysfunction in epilepsy. Previously, l was able to
recapitulate hyperexcitable electrographic features in organoids derived from a patient with Rett syndrome, a
neurological disorder highly associated with seizures and epilepsy. I have now generated cortical and
hippocampal organoids from hiPSCs harboring mutations in the SCN8A gene. This mutation results in a
severe childhood epilepsy. I have found that the SCN8A mutant cortex organoids have a highly hyperexcitable
pattern of physiological activity compared to controls, whereas the SCN8A mutant hippocampus lacks a
particular type of neural oscillation that is important for memory consolidation called a sharp wave ripple. This
finding suggests that the SCN8A mutation results in different physiological activity patterns in distinct brain
regions. Based on published studies, I hypothesize that this difference is primarily due to dysfunction of
excitatory neurons in the cortex versus inhibitory interneurons in the hippocampus. I will now use an array of
techniques such as calcium indicator imaging, extracellular recordings, immunohistochemistry, and
manipulation of the genetic background of excitatory and inhibitory neurons within the organoid to test this
hypothesis. To increase the rigor and generalizability of my data, I will use hiPSC from three different patients
with pathogenic SCN8A mutations. Finally, I will perform drug testing to further isolate the role of specific cell
types to the observed phenotypes and for consideration as therapeutic agents in patients. I expect that this will
both provide a blueprint for a novel methodology for epilepsy research and enhance our treatment and
understanding of epilepsy and neural circuit dysfunction resulting from SCN8A mutations.
项目摘要/摘要
癫痫病是一种严重而令人沮丧的疾病,也是一个重大的公共卫生问题。癫痫也是
没有医疗治愈的疾病,三分之一的患者对抗塞兹的反应
药物。在最严重的儿童期癫痫综合征中,癫痫发作的医学控制甚至可以是
更多挑战。新颖的实验平台有可能在推进我们的
了解和治疗癫痫。源自人类或诱导的脑官
多能干细胞是一种具有巨大潜力的新技术。尤其如此
严重的儿童发作,因为类器官非常适合对早期神经发育进行建模。器官是
3D结构概括了人脑的复杂元素,例如其层层组织和细胞
在人类皮质的所有六层中都看到的类型。由于它们可以是人类诱导的综合干细胞(HIPSC)
衍生,可以直接从患者组织产生类器官。器官技术的最新进展
已经产生了产生不同大脑区域的类器官,例如前脑皮质和
海马并与抑制性和兴奋性细胞类型的整合形成“融合”结构。
在以下建议中,我将利用这些进步并在我拥有的类器官平台上建立
最近开发的是建模脑电路的形成和功能障碍。以前,我能够
从RETT综合征患者衍生出的类器官中,概括了过度可见的电视功能,A
神经疾病与癫痫发作和癫痫高度相关。我现在已经产生了皮质和
来自SCN8A基因突变的HIPSC的海马器官。该突变导致
严重的童年癫痫。我发现SCN8A突变皮层类器官具有高度过度的
与对照组相比,体育活动的模式,而SCN8A突变体海马缺乏
特定类型的神经振荡对于记忆巩固很重要,称为尖锐的波浪纹波。这
发现表明SCN8A突变会导致不同大脑中不同的体育活动模式
地区。根据已发表的研究,我假设这种差异主要是由于功能障碍
海马中皮质与抑制性神经元的兴奋性神经元。我现在将使用一个数组
诸如钙指标成像,细胞外记录,免疫组织化学和等技术
操纵器官中兴奋和抑制性神经元的遗传背景来测试这一点
假设。为了提高数据的严格性和概括性,我将使用三个不同患者的HIPSC
带有致病性SCN8A突变。最后,我将进行药物测试以进一步隔离特定细胞的作用
观察到的表型的类型,并考虑为患者的治疗剂。我希望这会
两者都为癫痫研究的新方法提供了蓝图,并增强了我们的治疗方法
SCN8A突变引起的癫痫和神经回路功能障碍的理解。
项目成果
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{{ truncateString('RANMAL A SAMARASINGHE', 18)}}的其他基金
Utilizing Human Brain Organoids to Model the Differential Effects of SCN8A Mutation on Cortex and Hippocampus
利用人脑类器官模拟 SCN8A 突变对皮层和海马的不同影响
- 批准号:
10405560 - 财政年份:2021
- 资助金额:
$ 23.78万 - 项目类别:
Utilizing Human Brain Organoids to Model the Differential Effects of SCN8A Mutation on Cortex and Hippocampus
利用人脑类器官模拟 SCN8A 突变对皮层和海马的不同影响
- 批准号:
10301584 - 财政年份:2021
- 资助金额:
$ 23.78万 - 项目类别:
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