Investigation of Mechanosensory Signaling in the Pathogenesis of Traumatic Brain Injury in Human iPSC-derived Cortical Brain Organoids
人 iPSC 衍生的皮质脑类器官中机械感觉信号传导在创伤性脑损伤发病机制中的研究
基本信息
- 批准号:10548870
- 负责人:
- 金额:$ 4.23万
- 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:2021-01-15 至 2023-04-24
- 项目状态:已结题
- 来源:
- 关键词:3-Dimensional5&apos-AMP-activated protein kinaseAcuteAnimal ModelAnimalsAntisense OligonucleotidesAnxietyAstrocytesAutopsyBiochemicalBiologyBiophysical ProcessBloodBrainCase StudyCationsCell LineCellsChemicalsChronicClinicalComplexDataDementiaDiffuse Axonal InjuryDiseaseEdemaElderlyEnvironmental Risk FactorEtiologyEventFocused Ultrasound TherapyFrontotemporal DementiaFunctional disorderGene ExpressionGeneral PopulationGeneticGenetic TranscriptionGoalsHumanImmunoassayImmunologic FactorsIn VitroIncidenceIndividualInflammationInjuryInvestigationMeasuresMechanicsMental DepressionMetabolic dysfunctionMilitary PersonnelModelingMolecularMusMutationNerve DegenerationNeurodegenerative DisordersNeuronal InjuryNeuronsOrganoidsOutcomePathogenesisPathologicPathologyPatientsPhenotypePhosphotransferasesProcessRiskRoleSamplingSignal TransductionSurvival RateSymptomsSystemTBI PatientsTDP-43 aggregationTestingTimeTissue ModelTransgenic MiceTraumaTraumatic Brain InjuryUltrasonicsUnited StatesWestern BlottingWorkaxon injuryblood-brain barrier disruptioncell injurycell typecontrolled cortical impactdementia riskdisabilitydisease-causing mutationhyperphosphorylated tauimprovedin vivoin vivo Modelinduced pluripotent stem cellinjuredinnovationinsightknock-downmechanotransductionmortalitymouse modelnerve stem cellneuron lossneuronal survivalneuroprotectionnew therapeutic targetnovelpreservationpressurepreventprogramsprotein TDP-43responsesevere injurytau Proteinstau aggregationtau-1therapeutic targettranscriptome sequencingtranscriptomics
项目摘要
Project Summary/Abstract
Global incidence of Traumatic Brain Injury (TBI) is on the rise, particularly among athletes, military personnel,
and elderly citizens1. TBI represents a spectrum of mild to severe injuries that share many long-term pathologies
and clinical symptoms such as Tau and TDP43 pathology, axonal injury, neuronal death, and increased risk of
depression and neurodegenerative diseases2-6. Although end-stage pathologies are well characterized from
post-mortem samples, the molecular mechanisms contributing to injury remain poorly understood in part due to
the difficulty of studying live brains in human patients and the variable biophysical processes that occur between
patients. As a result, available treatment options remain limited and are largely ineffective61. Previous studies of
TBI conducted in animal models present with edema, inflammation, and blood-brain barrier disruption following
an induced trauma6,7. Although important to the pathophysiology of TBI, this complex cascade of events
complicates our ability to accurately understand cell autonomous injury mechanisms. Therefore, a reductionist
system to study the response of distinct cell types to TBI would be beneficial for identifying and targeting changes
that occur post-injury. To this end, we will utilize a 3-D cortical organoid culture system grown from human
induced Pluripotent Stem Cells (iPSCs) to elucidate cell autonomous mechanisms of injury and degeneration
caused by TBI8. We have developed a unique system of focused ultrasonic injury to mimic TBI in vitro which
recapitulates key pathologic and transcriptional features of in vivo models. This allows for detailed study of both
acute and chronic changes following an induced trauma, and provides a platform to integrate environmental and
genetic contributions to injury while preserving human-specific biology. Using this system, we will combine bulk
RNA-seq transcriptomic analysis with biochemical and immunoassays to uncover novel cell-type specific injury
mechanisms. Using iPSC lines from patients with neurodegenerative diseases, we will test how TBI modulates
genetically-induced disease mechanisms. Finally, we will test a mouse model of cortical controlled impact (CCI)
to validate our findings in vivo. This proposal will greatly enhance our understanding of specific injury
mechanisms in discrete cell types and may help to identify novel neuroprotective therapeutic targets.
项目摘要/摘要
全球创伤性脑损伤(TBI)的发病率正在上升,特别是在运动员、军事人员、
和老年公民1。脑损伤代表了一系列轻微到严重的损伤,这些损伤具有许多长期的病理特征。
和临床症状,如Tau和TDP43病理,轴突损伤,神经元死亡和增加的风险
抑郁症和神经退行性疾病2-6。尽管终末期病理的特征很好地表现为
在死后样本中,造成损伤的分子机制仍然知之甚少,部分原因是
研究人类患者活体大脑的困难以及发生在以下两种生物物理过程之间的差异
病人。因此,现有的治疗选择仍然有限,而且在很大程度上是无效的。以前的研究
在出现水肿、炎症和血脑屏障破坏的动物模型上进行脑损伤
诱发创伤6,7.尽管对脑外伤的病理生理学很重要,但这一复杂的事件级联反应
使我们准确理解细胞自主损伤机制的能力变得复杂。因此,一个简化论者
研究不同细胞类型对脑损伤的反应的系统将有助于识别和定位变化
是在受伤后发生的。为此,我们将利用从人类生长的三维皮质器官培养系统
诱导多能干细胞(IPSCs)阐明细胞损伤和退化的自主机制
由TBI8引起。我们开发了一种独特的体外模拟脑损伤的聚焦超声损伤系统,该系统
概述了体内模型的关键病理和转录特征。这样就可以对两者进行详细的研究
诱发创伤后的急性和慢性变化,并提供一个平台来整合环境和
基因对伤害的贡献,同时保存人类特有的生物学。使用这个系统,我们将合并批量
结合生化和免疫分析的RNA-seq转录分析揭示新的细胞类型特异性损伤
机制。使用神经退行性疾病患者的IPSC株,我们将测试TBI是如何调节的
基因导致的疾病机制。最后,我们将测试皮质受控撞击(CCI)的小鼠模型。
在活体内验证我们的发现。这一建议将极大地提高我们对具体伤害的理解
分离细胞类型的机制,并可能有助于确定新的神经保护性治疗靶点。
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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Joshua Berlind其他文献
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{{ truncateString('Joshua Berlind', 18)}}的其他基金
Investigation of Mechanosensory Signaling in the Pathogenesis of Traumatic Brain Injury in Human iPSC-derived Cortical Brain Organoids
人 iPSC 衍生的皮质脑类器官中机械感觉信号传导在创伤性脑损伤发病机制中的研究
- 批准号:
10334475 - 财政年份:2021
- 资助金额:
$ 4.23万 - 项目类别:
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