Elucidating the Endothelial-Smooth Muscle Cell Interactions in Marfan Syndrome Using iPSCs
使用 iPSC 阐明马凡氏综合症中内皮-平滑肌细胞的相互作用
基本信息
- 批准号:10597514
- 负责人:
- 金额:$ 4.77万
- 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:2021-12-31 至 2025-12-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAbnormal CellAffectAnimal ModelAortaApoptosisArchitectureBehaviorBindingBiocompatible MaterialsBiological AssayBlood VesselsCell CommunicationCellsCoculture TechniquesCollagenComplexConfocal MicroscopyConnective TissueConnective Tissue DiseasesContractile ProteinsDataDepositionDevelopmentDiameterDiseaseDisease ProgressionEarly DiagnosisElasticityElastinEndothelial CellsEndotheliumEnzyme-Linked Immunosorbent AssayEtiologyEventExposure toExtracellular MatrixExtracellular Matrix ProteinsFBN1FibrinFibronectinsGenesGenetic DiseasesGenetic studyHumanImpairmentIn VitroMMP2 geneMMP9 geneMarfan SyndromeMatrix MetalloproteinasesMechanicsMediatorMethodsMicrofibrilsModelingMutationNADPH Oxidase 1Paracrine CommunicationPathogenesisPathologyPatientsPerfusionPhenotypePhysiologicalProductionPropertyReactive Oxygen SpeciesRegulationSignal TransductionSmall Interfering RNASmooth Muscle MyocytesSourceTGFB1 geneTensile StrengthTestingTherapeuticTherapeutic InterventionTimeTissuesTransgenic MiceTubular formationVascular GraftVascular Smooth Muscleacetovanillonecell behaviordiagnostic biomarkerdifferentiation protocolfallsfastinsfibrillinfibulin-4hemodynamicsin vitro Modelin vivoinduced pluripotent stem cellinhibitorinsightinterdisciplinary approachmechanical forcemechanical propertiesmechanical signalmechanical stimulusmouse modelnew therapeutic targetnoveloverexpressionpressureprotein expressionresponsescaffoldshear stresstherapeutic developmenttherapeutic target
项目摘要
Project Summary
Marfan Syndrome (MFS) is a genetic disorder of the connective tissue caused by mutations in the fibrillin-
1(FBN1) gene. These mutations cause increased vascular smooth muscle cell (vSMC) apoptosis, increased
matrix metalloproteinase (MMP) expression, excessive elastin degeneration and collagen overexpression;
weakening the vascular architecture, impair hemodynamic regulation, and ultimately leading to severe vascular
complications. Primary cells, tissue explants, and transgenic mouse models suffer from insufficiencies that
inhibit development of novel insights into disease pathogenesis or potential therapeutics; warranting new
modeling platforms. Recent advances in biomaterials have generated vascular grafts that mimic properties of
the extracellular matrix (ECM) in the natural vasculature. Human induced pluripotent stem cells (hiPSC) are an
ideal, patient specific renewable cell source that provides an avenue to study how genetic diseases effect cell
mechanobiology, signaling and function to better development therapeutics. Here, using a natural fibrin-based
vascular graft and hiPSCs from patients with Marfan Syndrome, we aim to: (1) fully characterized both ECs
and contractile vSMCs from hiPSCs derived from Marfan patients, (2) study the responses of hiPSC-ECs to
shear force and hiPSC-vSMCs to circumferential strain, (3) study the impacts of mechanical forces (i.e. shear
force and circumferential strain) and paracrine signaling in a co-culture model, specifically reactive oxygen
species(ROS), on vSMC phenotype and rate of graft degradation using the fibrin-based vascular graft. Our
multidisciplinary approach underpinning this project will elucidate key mediators of MFS disease progression
towards early detection and therapeutic targets.
项目摘要
马凡氏综合征(MFS)是一种遗传性结缔组织疾病,由结缔组织蛋白突变引起,
1(FBN 1)基因。这些突变导致血管平滑肌细胞(vSMC)凋亡增加,
基质金属蛋白酶(MMP)表达、过度弹性蛋白变性和胶原过度表达;
削弱血管结构,损害血流动力学调节,并最终导致严重的血管
并发症原代细胞、组织外植体和转基因小鼠模型遭受不相容性,
抑制对疾病发病机理或潜在治疗方法的新见解的发展;
建模平台生物材料的最新进展已经产生了模拟血管移植物的性质的血管移植物,
细胞外基质(ECM)在天然血管系统。人类诱导多能干细胞(hiPSC)是一种
理想的,患者特异性的可再生细胞来源,为研究遗传疾病如何影响细胞提供了途径
机械生物学,信号和功能,以更好的发展治疗。在这里,使用天然纤维素为基础的
来自马凡综合征患者的血管移植物和hiPSC,我们的目标是:(1)充分表征两种EC
和收缩性vSMC,(2)研究hiPSC-EC对
剪切力和hiPSC-vSMCs对周向应变的影响,(3)研究机械力(即剪切力)
力和周向应变)和旁分泌信号,特别是活性氧
物种(ROS),对vSMC表型和移植物降解率使用纤维蛋白为基础的血管移植。我们
多学科的方法支持这个项目将阐明MFS疾病进展的关键介质
早期发现和治疗目标。
项目成果
期刊论文数量(0)
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{{ truncateString('Franklyn Hall', 18)}}的其他基金
Elucidating the Endothelial-Smooth Muscle Cell Interactions in Marfan Syndrome Using iPSCs
使用 iPSC 阐明马凡氏综合症中内皮-平滑肌细胞的相互作用
- 批准号:
10156365 - 财政年份:2021
- 资助金额:
$ 4.77万 - 项目类别:
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