Computational and experimental modeling of cell function in response to 3D oxygen transport in vitro.
细胞功能响应体外 3D 氧运输的计算和实验模型。
基本信息
- 批准号:9895842
- 负责人:
- 金额:$ 2.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-16 至 2020-11-15
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAnimal ModelArchitectureAreaBehaviorBiochemicalBiocompatible MaterialsBiological AssayBiologyBloodBlood VesselsCardiac OutputCell Culture TechniquesCell DeathCell DensityCell ProliferationCell SurvivalCell modelCell physiologyCellsCellular MorphologyCharacteristicsComputer ModelsConsumptionConvectionCoupledCuesDiffusionEngineeringEnvironmentEquationEvaluationExperimental ModelsExposure toGelGene ExpressionGene Expression ProfileGoalsHepG2HepaticHepatocyteHeterogeneityHydrogelsHypoxiaImageImpairmentIn VitroIncubatedJordanKnowledgeLengthLinkLiverMapsMeasurementMeasuresMetabolicMetabolismModelingOrganOxygenPatternPerfusionPhenotypePhysiologicalPlayPopulationPositioning AttributeProtocols documentationRadialRegenerative MedicineReproducibilityResearchResourcesRoleStructureSupporting CellTechniquesTherapeuticTimeTissue EngineeringTissue ModelTissuesTo specifyTrainingValidationVariantVisionbasebiofabricationcell behaviorcell typedensitydesigndesign and constructionexperimental studyhuman tissueimaging Segmentationin vivoinsightnoveloxygen transportpredictive modelingresponsespatiotemporalthree dimensional cell culturethree-dimensional modelingtranscriptome sequencing
项目摘要
Abstract
To advance regenerative medicine towards recapitulating the structures and functions of human tissues at physi-
ologic length scales and with relevant cell densities, strategies must be developed to meet their unrelenting metabolic
demands. In order to effectively and efficiently oxygenate functional engineered tissues, we must understand
how changes in oxygen tension modulate cell viability, proliferation, and phenotype. Decades of studying cell
cultures incubated under low oxygen levels have unveiled some aspects of the hypoxic response and many key in-
sights into its mechanism. Separately, an astonishing array of biomaterials have been developed which can support
cells in 3D environments and can recapitulate native cell morphologies and functions to a much greater extent than
2D culture. However, as emerging areas such as regenerative medicine have sought to incorporate cells within these
materials, new questions have emerged regarding the roles played by oxygen transport and hypoxia in directing the
density and function of the cell populations. Currently, we lack a comprehensive framework to describe and pre-
dict how cell populations will alter their densities and functions over time in the presence of spatiotemporally
heterogeneous oxygen gradients. We need to extend our knowledge of cellular responses to hypoxia into 3D and
we need to profile how tissue-specific cell functions are impacted by local oxygen cues. In this proposal, I and a sup-
porting team of experts in biomaterials, computational modeling, and liver biology will unify computational
models of hypoxic response with engineered model tissues to link oxygen transport with tissue function in
3D. Our findings will be incorporated into an experimentally validated model capable of predicting how cell popula-
tions change in density and function in response to specified oxygen gradients. Cellular responses to hypoxia will be
parameterized by cell-specific response functions and integrated with oxygen transport equations in an agent-based
computational model. We will fit parameters using advanced volumetric imaging and image segmentation along with
biochemical assays to map cellular markers of viability, proliferation, hypoxia, and phenotype within 3D hydrogels
containing HepG2 liver cells, a well-defined model cell type from a highly metabolic tissue. I hypothesize that our
closed-loop computational and experimental workflow will yield a scalable model of cell behavior at the tissue
level which captures previously unstudied functional responses to hypoxia. Finally, to broadly profile the phe-
notypic landscape of cells growing in the presence of oxygen gradients, we will use RNA sequencing to map spatial
zonation of cell phenotypes along axial and radial oxygen gradients in perfused hydrogels. Controlled encapsulation
of cells within hydrogels of reproducible architecture will enable us to evaluate these spatial patterns in gene expres-
sion with a degree of experimental control and reproducibility beyond the capabilities of in vivo approaches. Taken
together, these studies will provide fundamental insights into how cells respond to local oxygen gradients in
3D environments. Analysis of the spatial heterogeneity introduced by oxygen gradients is also expected to inspire
new paradigms for engineering zones of cell function within tissues.
摘要
项目成果
期刊论文数量(0)
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Ian S Kinstlinger其他文献
Ian S Kinstlinger的其他文献
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{{ truncateString('Ian S Kinstlinger', 18)}}的其他基金
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10606897 - 财政年份:2023
- 资助金额:
$ 2.9万 - 项目类别:
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