High-throughput nanoIEA-based Assay for Screening Immune Cell-Vascular Interactions
用于筛选免疫细胞-血管相互作用的基于 nanoIEA 的高通量测定法
基本信息
- 批准号:10592897
- 负责人:
- 金额:$ 21.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-19 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdherens JunctionAnimal GeneticsAnimal ModelAnimalsAutoimmune DiseasesBasement membraneBiological AssayBiologyBloodBlood - brain barrier anatomyBlood VesselsCOVID-19CategoriesCell AdhesionCell CommunicationCell-Cell AdhesionCellsCellular MorphologyChronicCoagulation ProcessCoculture TechniquesCommunicable DiseasesComplementDepositionDermalDiseaseDrug ScreeningElectrical ResistanceElectrodesEndothelial CellsEndotheliumEpitheliumExperimental ModelsExtravasationFunctional disorderGene ExpressionGoalsHumanImmuneImmune System DiseasesImmunityImmunologyImpairmentIn VitroInfectionInflammationInflammatoryIntercellular JunctionsInvestigationLesionLungLupusLymphaticMeasurementMeasuresMediatingMethodsModelingNaturePatternPericytesPermeabilityPharmaceutical PreparationsPhenotypePhysiologicalPlayPluripotent Stem CellsProcessRapid screeningReadingRoleScreening procedureSepsisSignal TransductionSiteSkinSystemSystems AnalysisTechnologyTherapeuticTimeVascular DiseasesVascular Permeabilitiescell behaviorcell motilityclinically relevantcytokinedrug candidateelectric impedanceendothelial dysfunctionexperienceglomerular filtrationhigh throughput screeningimprovedin vitro Modelin vivointerstitialknock-downlung microvascular endothelial cellsmigrationnanopatternnovelpathogenpersonalized medicinepolarized cellpreventscreeningtrafficking
项目摘要
PROJECT SUMMARY
Blood vessels play a central role in maintaining host immunity by transporting immune cells to sites of infection.
During the process, blood vessels experience endothelial junction remodeling to control vascular permeability
and immune cell extravasation. Under infection, blood vessels become permeable and allow immune cells to
extravasate and kill pathogens in the interstitium. Once the infection is resolved, permeable vessels become less
permeable and limit the number of interstitial immune cells. However, sometimes in inflammation, the remodeling
is perturbed, resulting in prolonged, hyper-permeable blood vessels. This vascular dysfunction contributes to
immune diseases, such as chronic inflammation, lupus, and autoimmune disease. It is known that endothelial
cell alignment is crucial to maintain intact cell-cell adhesion and promote junction maturation. Despite the
significance of the cell alignment in functional endothelium, currently available high-throughput methods, such
as real-time cell analysis (RTCA) and trans-epithelial/trans-endothelial electrical resistance (TEER) systems with
randomly seeded cells have not successfully measured cell impedance or electrical resistance through the in
vivo-like controlled endothelial cell morphology, alignment, and matured cell-cell junctions. Furthermore, the
current technologies lack pericyte co-culture with endothelial cells. In this proposal, we will develop a high-
throughput, high-content functional screening assay capable of faster drug screening and mechanistic studies
on blood vessel barrier function and immune cell extravasation. To achieve our goals, we will establish a
nanopatterned IEA-based functional assay for high-throughput phenotype screening of pericyte-covered
endothelium. To establish the nanopatterned IEA-based assay, we will determine conditions for junctional
maturation of human dermal and lung microvascular endothelial cells with or without pericytes, focusing on (i)
degree of cell alignment; (ii) expression of adherens junctions, polarization, and basement membrane markers;
(iii) vascular barrier function (Aim 1.1). We will then assess vascular gene expression profiles related to vessel
stabilization and immune cell adhesion. We will next evaluate immune cell extravasation through the endothelium
in the non-inflammatory condition to determine immune cell behaviors in steady-state blood vessels (Aim 1.2).
Next, we will validate the utility of the system for inflammation-induced blood vessel dysfunction. To achieve this
aim, we will examine the endothelial barrier function and immune cell extravasation in five different categories of
inflammatory cytokines and various levels of substrate stiffness considering skin and lung microenvironments
(Aim 2.1). Lastly, we will identify potential targets and drugs to reverse vessel dysfunction by focusing on
abrogation of the cytokine effect and the stiffness effect, separately or in combination (Aim 2.2). In summary, our
system will constitute a significant improvement over existing technologies as it represents a novel high-
throughput screening tool for functionally matured blood endothelium and their interactions with immune cells.
项目总结
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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Deok-Ho Kim其他文献
Deok-Ho Kim的其他文献
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{{ truncateString('Deok-Ho Kim', 18)}}的其他基金
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
- 批准号:
10502626 - 财政年份:2022
- 资助金额:
$ 21.17万 - 项目类别:
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
- 批准号:
10869757 - 财政年份:2022
- 资助金额:
$ 21.17万 - 项目类别:
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
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10861445 - 财政年份:2022
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$ 21.17万 - 项目类别:
A Human iPSC-based 3D Microphysiological System for Modeling Cardiac Dysfunction in Microgravity
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- 批准号:
10632929 - 财政年份:2022
- 资助金额:
$ 21.17万 - 项目类别:
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
- 批准号:
10636892 - 财政年份:2022
- 资助金额:
$ 21.17万 - 项目类别:
Transcriptomic Entropy to Quantify Maturation of PSC-Derived Cardiomyocytes
转录组熵量化 PSC 衍生心肌细胞的成熟
- 批准号:
10179233 - 财政年份:2021
- 资助金额:
$ 21.17万 - 项目类别:
Transcriptomic Entropy to Quantify Maturation of PSC-Derived Cardiomyocytes
转录组熵量化 PSC 衍生心肌细胞的成熟
- 批准号:
10378025 - 财政年份:2021
- 资助金额:
$ 21.17万 - 项目类别:
Transcriptomic Entropy to Quantify Maturation of PSC-Derived Cardiomyocytes
转录组熵量化 PSC 衍生心肌细胞的成熟
- 批准号:
10661492 - 财政年份:2021
- 资助金额:
$ 21.17万 - 项目类别:
DISEASE MODELING AND PHENOTYPIC DRUG SCREENING FOR DYSTROPHIC CARDIOMYOPATHY
营养不良性心肌病的疾病建模和表型药物筛选
- 批准号:
10164856 - 财政年份:2020
- 资助金额:
$ 21.17万 - 项目类别:
DISEASE MODELING AND PHENOTYPIC DRUG SCREENING FOR DYSTROPHIC CARDIOMYOPATHY
营养不良性心肌病的疾病建模和表型药物筛选
- 批准号:
10116566 - 财政年份:2020
- 资助金额:
$ 21.17万 - 项目类别:
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