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Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling

Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling
阐明心肌成纤维细胞对基质和脉管系统重塑的作用
批准号:
9909793
负责人:
EMILY OLSZEWSKI
金额:
$4.07万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-16 至 2023-05-15
关键词:
3-DimensionalAffectAgingAortic Valve StenosisApoptosisAreaArteriesArtificial HeartAtomic Force MicroscopyAutomobile DrivingBiochemicalBiometryBlood VesselsCardiacCardiac MyocytesCardiovascular PhysiologyCause of DeathCellsCharacteristicsChemical StructureChemicalsChemistryCollagenCollagen FiberConfocal MicroscopyContractsCoronaryCuesDataDepositionDiseaseEndothelial CellsEndotheliumEngineeringEnvironmentExtracellular MatrixExtracellular SpaceFibroblastsFibrosisFreeze DryingGelGene ActivationGenerationsGenetic ModelsGoalsHeartHeart DiseasesHeart failureHypertensionHypertrophyImageIn VitroInjuryLectinLeftLengthLiquid ChromatographyLongitudinal StudiesMAP2K6 geneMapsMeasurementMeasuresMechanicsMediatingMethodsModelingMolecularMusMyocardial InfarctionMyofibroblastNatureOperative Surgical ProceduresOrganPathway interactionsPerfusionPerivascular FibrosisPhenotypePhosphotransferasesPhysiologicalPhysiologyPreparationProcessPropertyProtein KinaseProteomicsPumpRegulationRoleSignal TransductionStimulusStressStretchingStructureSystemTherapeuticThree-Dimensional ImageTimeTissuesTractionTransgenesTransgenic MiceVascular remodelingVentricularWorkblebbistatincell growthcell motilitycell typecombinatorialcoronary fibrosisdensityexperimental studyextracellularheart functionimage reconstructionin vitro Modelin vivoin vivo Modelinterstitialknock-downmathematical modelmechanical propertiesmicroscopic imagingmigrationoverexpressionpreservationpressureresponsescaffoldsecond harmonictandem mass spectrometrytwo-photon

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中文摘要
翻译
在每一种形式的心脏病,分泌细胞外基质(ECM)的激活 成纤维细胞或肌成纤维细胞导致心脏纤维化。纤维化妨碍依从性, 泵送功能,最终导致心力衰竭,由于左心室扩张和丧失 机械功能关于内皮细胞和血管适应性的了解很少, 环境或局部力学和化学如何影响体内血管结构和流动。 组合成纤维细胞和ECM与内皮细胞的机械和化学串扰是 未知此外,旨在评估血管对细胞外基质的适应性的体外模型, 环境缺乏生理相关ECM,而是提供外源ECM 优化变量控制的组件。用于体内细胞特异性表型分析的系统, 操纵将允许在器官水平上的受控扰动同时保持相关, 随着时间的推移天然ECM重塑。因此,我建议检查转基因小鼠的心脏 成纤维细胞特异性过表达组成型活性丝裂原活化蛋白激酶 激酶6(MKK 6)研究血管重塑与成纤维细胞和ECM, 秘密这些小鼠之前曾被证明在注射后会出现间质和血管周围纤维化 16-20周的MKK 6基因激活,没有损伤刺激,作为有效的 间质纤维化模型在衰老、高血压、主动脉 狭窄和其他心脏疾病。重要的是,在这些疾病中看到的重塑 不涉及心肌细胞的大量损失,如心肌梗死,而是 保守的成纤维细胞表型变化,细胞外空间改变,和/或限制性的 随着时间的推移血管流量。类似地,操纵MKK 6通路允许过表达 或敲低心脏成纤维细胞活化,对应于ECM增加或不能 分泌ECM作为对刺激响应。首先,我建议研究 ECM的生物化学、结构和机械特性以及宏观和微观特性。 微血管对激活、静止和对照心脏成纤维细胞表型的反应 vivo.其次,具有受控成纤维细胞和ECM的三维血管样结构将 作为体外平台设计,以确定血管重塑的分子调节剂 由微环境线索引起的。组合信号的影响将通过以下方式解决: 整体表征沿着简化方法。这项工作的目标是告知心脏 通过提供引导心脏血管重塑的靶点来治疗。
英文摘要
In every form of heart disease, the secretion of extracellular matrix (ECM) by activated fibroblasts, or myofibroblasts, results in cardiac fibrosis. Fibrosis impedes compliance and pumping function, ultimately leading to heart failure due to left ventricular dilation and loss of mechanical function. Little is known about endothelial cell and vessel adaptations to the environment or how local mechanics and chemistry impact vessel structure and flow in vivo. Combinatorial fibroblast and ECM mechanical and chemical crosstalk with endothelial cells are unknown. Moreover, in vitro models aiming to assess vascular adaptations to an extracellular environment lack physiologically relevant ECMs and instead provide exogenous ECM components to optimize control of variables. A system for in vivo, cell-specific phenotypic manipulation will allow for controlled perturbations at an organ level while maintaining relevant, native ECM remodeling over time. Thus, I propose to examine transgenic mice with cardiac fibroblast-specific overexpression of a constitutively active mitogen-activated protein kinase kinase 6 (MKK6) to study vascular remodeling with respect to the fibroblasts and the ECM they secrete. These mice were previously shown to develop interstitial and perivascular fibrosis after 16-20 weeks of the MKK6 gene activation without an injury stimulus, serving as an effective model of the interstitial fibrosis preserved across the results of aging, hypertension, aortic stenosis, and other diseases of the heart. Importantly, the remodeling seen in these diseases does not involve a massive loss of cardiomyocytes, as in a myocardial infarction, but rather a conserved fibroblast phenotypic change, an altered extracellular space, and/or restricted vascular flow over time. Similarly, manipulation of the MKK6 pathway allows for overexpression or knockdown of cardiac fibroblast activation, corresponding to increased ECM or the inability to secrete ECM as a response to a stimulus, respectively. First, I propose to study the biochemical, structural, and mechanical properties of the ECM as well as the macro- and microvascular responses to activated, quiescent, and control cardiac fibroblast phenotypes in vivo. Second, three-dimensional vessel-like structures with controlled fibroblasts and ECMs will be engineered as in vitro platforms to define the molecular regulators of vascular remodeling induced by microenvironmental cues. The effects of combined signaling will be resolved by global characterization along with a reductionist method. The goal of this work is to inform heart therapies by providing targets for steering cardiac vascular remodeling.
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Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling
  • 批准号:
    10431762
  • 项目类别:
  • 资助金额:
    $4.12万
  • 财政年份:
    2020
  • 负责人:
    EMILY OLSZEWSKI
  • 依托单位:
Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling
  • 批准号:
    10469639
  • 项目类别:
  • 资助金额:
    $0.26万
  • 财政年份:
    2020
  • 负责人:
    EMILY OLSZEWSKI
  • 依托单位:
海外基金