Piezo channel activation and mechanotransduction in chondrocytes during traumatic injury
创伤性损伤期间软骨细胞的压电通道激活和机械转导
基本信息
- 批准号:10001969
- 负责人:
- 金额:$ 7.01万
- 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:2018-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAccidentsAcuteAmericanAnabolismApoptosisAthletic InjuriesAtomic Force MicroscopyAttentionAutomobile DrivingBiomimeticsCalciumCartilageCationsCell SurvivalCell membraneCellsCellular MechanotransductionCellular MembraneChondrocytesComplexDegenerative polyarthritisDiseaseElementsEncapsulatedEnvironmentExposure toFundingGene ExpressionGene Expression RegulationGenesGrantHomeostasisHydrogelsHydrostatic PressureInflammatoryInjuryIon ChannelKnowledgeLinkMammalsMechanical StimulationMechanicsMediatingMediator of activation proteinMembraneModelingOutcomePathway interactionsPatientsPatternPeptide HydrolasesPharmaceutical PreparationsPharmacotherapyPhysiologicalPhysiologyPiezo 1 ion channelPiezo 2 ion channelPiezo ion channelsPreventionResolutionRoleSecondary toSepharoseSignal TransductionSystemTissue EngineeringTissuesTrainingTraumatic injuryVisualizationWorkarticular cartilagecareercartilage degradationcytokinedrug developmentenzyme biosynthesisexperienceexperimental studyfluid flowjoint injuryjoint loadingknock-downmechanical loadmechanotransductionmultidisciplinarynovelpatch clamppreventresponsetherapy developmenttranscriptome sequencing
项目摘要
ABSTRACT
Nearly half of all joint injuries result in symptomatic post-traumatic osteoarthritis (PTOA) within 5 years of
injury. Supraphysiologic mechanical loading of the joint, such as that occurring from a sports injury or accident,
is believed to be mechanically perceived by the chondrocytes residing within the articular cartilage, initiating a
cascade of catabolic and inflammatory gene expression and the synthesis of proteases and cytokines which
accelerate the cartilage degradation present in symptomatic PTOA. Despite the extensive characterization of
the osteoarthritic chondrocytes present in PTOA, the mechanisms by which chondrocytes perceive excessive
mechanical loading, and the pathways linking injury mechanics to catabolic gene expression, are unknown.
Currently there are no disease modifying osteoarthritis drugs (DMOADs) to treat, prevent, or delay the
degradation of cartilage following injury. The recently discovered Piezo channels (Piezo1 and Piezo2) are the
first class of ion channels directly responsive to mechanical stimulation in mammals. Our lab found that the
Piezo channels selectively transduce high cellular deformation into intracellular signals, suggesting a novel
mechanism through which supraphysiologic loading may directly initiate and propagate the catabolic gene
expression of PTOA. Fundamental questions remain surrounding the role of Piezo activation in the
chondrocyte’s response to mechanical loading, including: what threshold for cellular deformation activates the
Piezo channels and how is this deformation is perceived in a three-dimensional environment? Isolating and
identifying the deformation modes of chondrocyte mechanotransduction would be a major advance in our
understanding of cellular mechanotransduction and the physiology of cartilage. Additionally, the influence on
gene expression of mechanically-activated Piezo channels is unknown. Overall, this proposal seeks to
establish the fundamental modes of mechanical activation of Piezo channels in chondrocytes and the
downstream implications of Piezo activation. Specifically, in Aim 1 we will identify the cellular deformation
thresholds driving Piezo activation and how loading a biomimetic three-dimensional hydrogel system elicits
chondrocyte Piezo activation. Aim 2 will then determine the role of Piezos on mechanically-activated gene
expression. Together, completing these exciting aims will be accomplished with a coordinated experimental
and computational approach. Funding of this grant will provide me a multidisciplinary experience to advance
my computational and experimental training in tissue engineering to that of chondrocyte mechanobiology and
gene regulation.
摘要
项目成果
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