A developmental engineering toolbox for large-scale tissue engineering
用于大规模组织工程的发育工程工具箱
基本信息
- 批准号:10456084
- 负责人:
- 金额:$ 39.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdhesivesAffectBreastCRISPR screenCellsChronic Kidney FailureComplexCongenital AbnormalityDNADevelopmentDevelopmental ProcessDiseaseDuct (organ) structureEngineeringExtracellular MatrixGelHomeostasisIn VitroKidneyKidney DiseasesLocationLungMethodsModelingMorphogenesisOrganOrganoidsPatternPharmacotherapyPhenotypePhilosophyPluripotent Stem CellsPositioning AttributeProstateRenal functionResearch PersonnelResolutionSeedsShapesStandardizationStructureSystemTechnologyTissue EngineeringTissue ModelTissuesUrinary tractVariantbasebody systemcell typecollecting tubule structuregenetic risk factorhuman diseasehuman tissuetissue support framewhole genome
项目摘要
PROJECT SUMMARY
Many diseases in complex, hierarchically organized tissues such as the breast, lung, and prostate have been
difficult to address, because they are a product of complex multicellular dynamics. For example, congenital
diseases of the kidney are staggeringly common. Around a third of all birth defects are associated with
problems in kidney and urinary tract development, but researchers have few options for capturing the full
functional complexity of this organ system outside of the body. This is because current kidney models are
either 2D, single cell-type approximations, or are organoid models with more cellular diversity, but with little of
the long-range spatial structure that is crucial for kidney function.
The Hughes lab aims to solve two critical engineering barriers to the development of better in
vitro human tissue models. First, we aim to standardize and vastly increase the throughput of organoid-
based phenotypic screens related to human disease. Second, we aim to bring an entirely new philosophy to
tissue engineering, in which tissue scaffolds are not built in final form, but rather as immature “seeds” that are
guided through developmental transitions in structure that mimic those of their target tissue. These transitions
morph flat tissue scaffolds into final tissue forms that achieve defined shapes, cell distributions, and ECM
compaction and alignment patterns in 3D that establish a new way of building hierarchical tissues like the
kidney.
To the first aim, we propose to re-engineer our cell DNA “velcro” cell and organoid patterning
technology. This technology allows us to precisely pattern multiple cell types with single-cell resolution at the
interface with organotypic gel layers, yet its throughput is currently limited. We will apply a photopatterning
approach in which cell-adhesive ssDNA strands can be patterned in millions of locations simultaneously, a key
requisite for whole-genome organoid screens. Secondly, we propose high-throughput pluripotent stem cell
patterning and culture technologies that reduce inter-organoid variation, to enable whole genome CRISPR-
based screening for genetic risk factors of disease, using kidney organoids as a prototypical system. To the
second aim, we build upon our recent description of dynamic tissue scaffolds to position organoids in
3D using autonomously folding gels that couple their niches through tracts of dynamically remodeled ECM.
Using these centimeter-scale, 3D organoid patterning capabilities, we envision an analogy between the
branching pattern of the kidney collecting duct network and the edge networks of “flasher” origami patterns. By
controlling the morphogenesis of these patterns, we seek to engineer the progressive formation of a
contiguous collecting duct network between locally self-organizing tissue niches. Rather than directly
building tissues in a final, yet immature form, we believe that building hierarchical tissues by guided
morphogenesis presents a transformative opportunity for modeling tissue homeostasis and disease.
项目摘要
复杂的,分层组织的组织中的许多疾病,例如乳房,肺和前列腺
很难解决,因为它们是复杂的多细胞动力学的产物。例如,先天性
肾脏的疾病非常普遍。大约三分之一的出生缺陷与
肾脏和尿路发展中的问题,但研究人员几乎没有选择捕获完整的选择
该器官系统在体外的功能复杂性。这是因为当前的肾脏模型是
2D,单细胞类型近似,或者是具有更细胞多样性的器官模型,但很少
对于肾功能至关重要的远程空间结构。
休斯实验室旨在解决两个关键的工程障碍,以开发更好
体外人体组织模型。首先,我们的目标是标准化和大大增加器官的吞吐量
基于与人类疾病有关的表型筛选。其次,我们旨在将一种全新的哲学带给
组织工程,其中组织支架不是最终形式的,而是不成熟的“种子”
通过模拟其目标组织的结构的发展过渡的指导。这些过渡
将平坦的组织支架变成最终组织形式,以实现定义的形状,细胞分布和ECM
3D中的压实和对齐方式建立了一种新的构建等级组织的方式
肾。
为了第一个目的,我们建议重新设计细胞DNA“魔术贴”细胞和器官图案
技术。这项技术使我们能够精确地对多种单元类型进行单细胞分辨率的多种细胞类型
与有机凝胶层的接口,但其吞吐量目前受到限制。我们将应用一个照相。
可以简单地在数百万个位置将细胞粘附性ssDNA链图案化的方法,一个钥匙
全基因组器官筛选的必要条件。其次,我们提出了高通量多能干细胞
减少甲基机间变异的图案和文化技术,以使整个基因组CRISPR-
基于筛查疾病的遗传危险因素,使用肾脏器官作为原型系统。到
第二个目的,我们以最新的描述动态组织支架来定位器官
3D使用自主折叠凝胶,通过动态重塑的ECM进行将壁细分融合在一起。
使用这些厘米尺度的3D器官图案化功能,我们设想了一个类比
肾脏收集导管网络和“闪光灯”折纸图案的边缘网络的分支模式。经过
控制这些模式的形态发生,我们试图设计
局部自组织的组织壁ni之间的连续收集导管网络。而不是直接
以最终但不成熟的形式建造组织,我们认为通过指导构建分层组织
形态发生提供了对组织稳态和疾病进行建模的变革机会。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Alex Hughes其他文献
Alex Hughes的其他文献
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{{ truncateString('Alex Hughes', 18)}}的其他基金
Engineering induction and assembly of human kidney tissue
人体肾脏组织的工程诱导与组装
- 批准号:
10419434 - 财政年份:2022
- 资助金额:
$ 39.81万 - 项目类别:
Engineering induction and assembly of human kidney tissue
人体肾脏组织的工程诱导与组装
- 批准号:
10598587 - 财政年份:2022
- 资助金额:
$ 39.81万 - 项目类别:
A developmental engineering toolbox for large-scale tissue engineering
用于大规模组织工程的发育工程工具箱
- 批准号:
10703388 - 财政年份:2019
- 资助金额:
$ 39.81万 - 项目类别:
A developmental engineering toolbox for large-scale tissue engineering
用于大规模组织工程的发育工程工具箱
- 批准号:
9795761 - 财政年份:2019
- 资助金额:
$ 39.81万 - 项目类别:
A developmental engineering toolbox for large-scale tissue engineering
用于大规模组织工程的发育工程工具箱
- 批准号:
10222724 - 财政年份:2019
- 资助金额:
$ 39.81万 - 项目类别:
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