Establishment of a human, age-specific model for axon growth and regeneration studies
建立用于轴突生长和再生研究的人类特定年龄模型
基本信息
- 批准号:9978418
- 负责人:
- 金额:$ 44.1万
- 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:2020-05-01 至 2022-10-31
- 项目状态:已结题
- 来源:
- 关键词:ASCL1 geneAdultAffectAgeAnimal ModelAnimalsAxonBehaviorBiologicalBirthBypassCell AgingCell Culture SystemCell MaintenanceCellsClinical TrialsCommunitiesDNA DamageDevelopmentDoxycyclineEmbryoEncyclopedia of DNA ElementsEnvironmentEpigenetic ProcessExpression ProfilingFibroblastsGene ExpressionGenesGenetic TranscriptionGlutamatesGrowthHomologous GeneHumanIn VitroInjuryKnock-outLeadLengthLifeMaintenanceMeasuresMedicalMethodsMitochondriaModelingMotor NeuronsMusNatural regenerationNeonatalNeuraxisNeuronsPTEN geneParalysedPathway interactionsPhenotypePlayPopulationProtocols documentationResearchResearch PersonnelResourcesRodentRoleSomatic CellSpinal cord injurySystemTestingTreatment EfficacyValidationWorkagedaxon growthaxon regenerationcell agedisabilityexcitatory neuronhuman modelhuman tissuein vitro Modelinduced pluripotent stem celljuvenile animalknock-downnoveloverexpressionpluripotencypostnatalpsychologicregenerativeresponsescreeningsocialstem cellstargeted treatmenttelomeretherapeutic targettooltranscription factortransdifferentiationyoung adult
项目摘要
Human spinal cord injury leads to life-long disability, with limited treatment options despite decades of
research in rodents. Recent evidence indicates that there are fundamental differences in gene expression
between human and mouse, suggesting a critical need for identification of novel or human-specific candidates
as targets to increase axon regeneration following spinal cord injury. Additionally, in vitro studies of axon
growth are typically performed in neurons from embryonic or young postnatal rodents, ages with increased
intrinsic growth ability, and a very different transcriptional landscape from adult neurons. Thus, we propose to
create an age-relevant, human model for axon growth and regeneration.
Recent technological advances now allow for human adult somatic cells to be reprogrammed into stem
cells, and then differentiated into neurons. However, reprogramming these cells through pluripotency has been
shown to erase the “age” of the original cell, resulting in a more embryonic identity of the resulting neuron.
Using a direct reprogramming protocol, we will transdifferentiate neonatal, ~35 year old, and ~70 year old
human somatic cells directly into neurons through overexpression of specific neuronal factors, allowing for
maintenance of the cell’s biological age identity. We will determine the maintenance of age in these cells at the
level of the epigenetic age signature, gene expression, and markers of cellular aging. As the first study of axon
growth in age-maintained human neurons, we will characterize the basal axon growth behavior on permissive
and inhibitory substrates to identify if age plays a role in human axon growth ability. To test this new resource,
we will target 20 different genes and pathways previously identified in other species to regulate axon growth for
their conservation in function in human neurons. In rodents it has recently been shown that certain axon growth
modifiers such as PTEN knockout, do not function similarly in aged animals as young animals (Geoffroy et al,
2016). Thus, we will utilize our age-maintained human iNs to determine if age drives changes in axon growth
phenotypes.
Completion of this research will 1) establish a new human, age-relevant cell culture system for axon
growth studies, 2) identify genes and their regulators that have conserved functions in human neurons, and 3)
determine the role age plays in axon growth ability. Identification of translational targets specifically in human
neurons ultimately may lead to the development of effective therapeutic targets for human spinal cord injury.
人类脊髓损伤导致终身残疾,尽管数十年来,
啮齿动物的研究。最近的证据表明,基因表达存在根本差异,
人和小鼠之间的差异,表明迫切需要鉴定新的或人类特异性的候选物
作为增加脊髓损伤后轴突再生的靶点。此外,轴突的体外研究
生长通常在来自胚胎或年轻的出生后啮齿动物的神经元中进行,随着年龄的增加,
内在的生长能力,和一个非常不同的转录景观从成年神经元。因此,我们建议
建立一个与年龄相关的人类模型来研究轴突的生长和再生。
最近的技术进步现在允许人类成年体细胞重新编程为干细胞
细胞,然后分化成神经元。然而,通过多能性对这些细胞进行重编程,
显示消除了原始细胞的“年龄”,导致产生的神经元更具胚胎特征。
使用直接重编程协议,我们将转分化新生儿,~35岁,和~70岁
通过过表达特定的神经元因子,将人类体细胞直接转化为神经元,
维持细胞的生物学年龄特性。我们将确定这些细胞中年龄的维持,
表观遗传年龄特征、基因表达和细胞衰老标志物的水平。作为第一个对轴突的研究
在年龄维持的人类神经元的生长,我们将表征基础轴突生长行为的许可
和抑制底物来鉴定年龄是否在人类轴突生长能力中起作用。为了测试这个新资源,
我们将靶向20种不同的基因和途径,这些基因和途径以前在其他物种中发现,
它们在人类神经元功能中的保守性。在啮齿类动物中,最近的研究表明,某些轴突的生长
修饰物如PTEN敲除在老年动物中的功能与在年轻动物中的功能不同(Geoffroy等,
2016年)。因此,我们将利用我们的年龄保持人类iNs,以确定是否年龄驱动轴突生长的变化
表型
这项研究的完成将1)建立一个新的人类,年龄相关的轴突细胞培养系统
生长研究,2)鉴定在人类神经元中具有保守功能的基因及其调节剂,以及3)
确定年龄在轴突生长能力中的作用。人类特异性翻译靶点的鉴定
神经元最终可能导致人类脊髓损伤的有效治疗靶点的发展。
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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Darcie Leann Moore其他文献
Darcie Leann Moore的其他文献
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{{ truncateString('Darcie Leann Moore', 18)}}的其他基金
Label-free, live-cell classification of neural stem cell activation state and dynamics
神经干细胞激活状态和动力学的无标记活细胞分类
- 批准号:
10863309 - 财政年份:2023
- 资助金额:
$ 44.1万 - 项目类别:
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