Leveraging 3D bioprinted organoid constructs to pattern and model human brain development
利用 3D 生物打印类器官结构来模拟人类大脑发育
基本信息
- 批准号:10380006
- 负责人:
- 金额:$ 65.05万
- 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:2021-04-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAchievementAddressArchitectureBathingBehaviorBenchmarkingBiocompatible MaterialsBiologicalBiological AssayBiological ModelsBiomechanicsBiomedical EngineeringBrainCell Differentiation processCell SurvivalCellsComplexCuesCustomDevelopmentDiffusionDistressDorsalElectrophysiology (science)ElementsEmotionalEncapsulatedEnvironmentExtracellular MatrixFinancial HardshipGenerationsGeometryGlycoproteinsGlycosaminoglycansGoalsHealthHistologicHistologyHumanImageIn VitroIndividualKineticsLaboratoriesLeadershipLightMeasurementMeasuresMethodsModelingMolecularNanotechnologyNatureNervous System PhysiologyNeurodevelopmental DisorderNeuronsNeurosciencesOrganoidsOutputPatternPhysiologicalPhysiologyPropertyProteinsProteoglycanProtocols documentationPublic HealthReproducibilityResearchResolutionRoboticsRoleSHH geneSchemeShapesSignal TransductionSignaling MoleculeSystemTechnologyTestingTissue EngineeringTissue constructsTissuesWorkbioinkbioprintingbrain parenchymabrain tissuecell behaviorcostcraniumdesignextracellularhuman modelhuman stem cellshydrogel scaffoldin vitro Modelinduced pluripotent stem cellinnovationmatrigelmorphogensnanonanoparticlenervous system developmentnervous system disorderneural circuitneural modelneurodevelopmentnovelphotoactivationphysical propertypreventrelating to nervous systemscaffoldsingle-cell RNA sequencingskillssmall moleculesmoothened signaling pathwayspatiotemporalstem cell fatestem cell modelstem cellssuccesssynergismtool
项目摘要
Project Summary
In addition to significant human distress, neurological disorders cost the U.S. economy more than $1.5 trillion
per year—8.8 percent of the gross domestic product. This physical, emotional and financial burden underscores
the potential benefit from developing innovative platforms to study brain development, physiology, and
associated diorders. The advent of human induced pluripotent stem cell (hiPSC)-derived 3D cortical organoid
cultures has shown great promise as a model system, yet there remain a number of technical limitations that
have stymied their ability to recapitulate critical non-cell autonomous aspects of human brain development.
These components include extrinsic influences of the extracellular matrix (ECM), skull, and axial morphogen
gradients that together help shape and diversify regions of the developing brain.
Currently, standard organoid protocols involve embedding organoids in Matrigel droplets or in suspended bath
culture, which prevents reproducible user-control of the extracellular environment. This limits the ability to create
morphogen gradients that topographically polarize stem cells, or to ask how molecular and physical properties
of the ECM outside the brain parenchyma guide neurodevelopment. To address these challenges, we propose
developing 3D bioprinted cortical organoid constructs that recapitulate key microenvironmental cues of native
brain tissue. This project builds upon our recent technological achievements, enabling embedded bioprinting of
custom tissue constructs at high spatial resolution (20 µm) specifically designed for long-term organoid culture.
Our goal is to bioprint cortical brain organoids into 3D scaffolds with customizable molecular and
physiomechanical compositions. The synergy of brain organoid and bioprinting technologies provides a nearly
unlimited potential to manipulate extrinsic developmental cues of a complex multicellular human model system.
We will pursue two integrated Specific Aims using the multi-PI leadership mechanism to combine complementary
research skills and expertise in the Sloan (neurodevelopment) and Serpooshan (tissue engineering)
laboratories. In Aim 1, we will decouple the molecular composition and physical stiffness paramaters of the
ECM, and ask how these factors influence neural development, differentiation, maturation and architecture. In
Aim 2, we will use three separate approaches to generate a stable morphogen gradient within bioprinted
constructs, which we will use to induce intra-organoid polarization of both dorsal (pallial) and ventral
(subpallial) regional identities. Together, these approaches offer a novel platform for 3D stem cell modeling that
could be applied broadly to numerous systems and usher a new generation of neurodevelopmental modeling.
项目摘要
除了严重的人类痛苦,神经系统疾病给美国经济造成的损失超过1.5万亿美元
占国内生产总值的8.8%。这种身体、情感和经济负担凸显了
开发创新平台研究大脑发育、生理学和
相关双目人类诱导多能干细胞(hiPSC)衍生的3D皮质类器官的出现
文化作为一种模式系统已经显示出很大的希望,但仍然存在一些技术限制,
已经阻碍了它们重现人类大脑发育的关键非细胞自主方面的能力。
这些成分包括细胞外基质(ECM)、头骨和轴向形态原的外在影响
这些梯度共同帮助塑造和多样化发育中的大脑区域。
目前,标准的类器官方案涉及将类器官包埋在基质胶液滴中或悬浮浴中,
培养,这阻止了细胞外环境的可再现的用户控制。这限制了创造的能力
形态发生梯度,拓扑学地覆盖干细胞,或者问分子和物理性质如何
脑实质外的ECM引导神经发育。为了应对这些挑战,我们建议
开发3D生物打印的皮质类器官构建体,重现原生微环境的关键线索
脑组织该项目建立在我们最近的技术成就之上,使嵌入式生物打印成为可能。
高空间分辨率(20 µ m)的定制组织构建体,专为长期类器官培养而设计。
我们的目标是将大脑皮质类器官生物打印成3D支架,
物理力学成分脑类器官和生物打印技术的协同作用提供了一个近
操纵复杂多细胞人类模型系统的外在发育线索的无限潜力。
我们将追求两个综合的具体目标,使用多PI领导机制,以联合收割机互补
斯隆(神经发育)和Serpooshan(组织工程)的研究技能和专业知识
laboratories.在目标1中,我们将解耦的分子组成和物理刚度参数的
ECM,并询问这些因素如何影响神经发育,分化,成熟和架构。在
目标2,我们将使用三种不同的方法在生物打印中产生稳定的形态梯度。
结构,我们将使用它来诱导背侧(苍白)和腹侧的类器官内极化
(subpallial)区域身份。总之,这些方法为3D干细胞建模提供了一个新的平台,
可以广泛应用于许多系统,并迎来新一代的神经发育建模。
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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Vahid Serpooshan其他文献
Vahid Serpooshan的其他文献
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{{ truncateString('Vahid Serpooshan', 18)}}的其他基金
Leveraging 3D bioprinted organoid constructs to pattern and model human brain development
利用 3D 生物打印类器官结构来模拟人类大脑发育
- 批准号:
10184225 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Leveraging 3D bioprinted organoid constructs to pattern and model human brain development
利用 3D 生物打印类器官结构来模拟人类大脑发育
- 批准号:
10550132 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Myocardial remuscularization by cardiac patch delivery of epicardial FSTL1 and CCND2 overexpressing cardiomyocytes
通过心脏补片递送心外膜 FSTL1 和 CCND2 过表达心肌细胞进行心肌再肌化
- 批准号:
10375894 - 财政年份:2016
- 资助金额:
$ 65.05万 - 项目类别:
Supplement of HL131017: Myocardial remuscularization by cardiac patch delivery of epicardial FSTL1 and CCND2 overexpressing cardiomyocytes
HL131017 补充:通过心外膜 FSTL1 和 CCND2 过表达心肌细胞的心脏补片递送进行心肌再肌化
- 批准号:
10797360 - 财政年份:2016
- 资助金额:
$ 65.05万 - 项目类别:
Molecular and Cellular Mechanisms of Neonatal Cardiac Development and Repair
新生儿心脏发育和修复的分子和细胞机制
- 批准号:
9024262 - 财政年份:2016
- 资助金额:
$ 65.05万 - 项目类别:
Myocardial remuscularization by cardiac patch delivery of epicardial FSTL1 and CCND2 overexpressing cardiomyocytes
通过心脏补片递送心外膜 FSTL1 和 CCND2 过表达心肌细胞进行心肌再肌化
- 批准号:
10538614 - 财政年份:2016
- 资助金额:
$ 65.05万 - 项目类别:
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