Role of Glucose metabolism in Chondrocyte Mechanotransduction
葡萄糖代谢在软骨细胞力转导中的作用
基本信息
- 批准号:10474766
- 负责人:
- 金额:$ 20.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAffectAgeAgingAmino AcidsAnimalsBasic ScienceBiochemical ReactionBiologicalBiological AssayBiological ModelsBiologyBody Weight decreasedCarbonCartilageCartilage MatrixCellsChondrocytesCitric Acid CycleClinicalComplexDataDegenerative polyarthritisDeteriorationDrug TargetingElderlyEnergy-Generating ResourcesEnvironmentEnzyme Inhibitor DrugsEvaluationExerciseFutureGlucoseGlutamineGlycolysisGoalsHealthHistopathologyHumanImpairmentIn VitroIndividualInflammatory ResponseInjuryIsotope LabelingIsotopesJointsKnowledgeLinkLiquid substanceMass Spectrum AnalysisMechanical StimulationMechanicsMediatingMetabolicMetabolic PathwayMetabolismMethodsMissionModelingMolecularMotionMovementMusMusculoskeletal SystemNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNon-Essential Amino AcidOutcomePainPathogenesisPathologyPathway interactionsPatientsPatternPentosephosphate PathwayPeriodicityPharmaceutical PreparationsPhysiologicalProcessProductionProteinsQuality of lifeReactionReference ValuesRegulationReplacement ArthroplastyRespirationRoleRunningSignal TransductionSourceStainsStimulusSymptomsSynovial MembraneSynovial jointSystems BiologyTestingTimeTissuesTranslatingTranslationsUnited States National Institutes of HealthWalkingblood glucose regulationbonebone cellcartilage repaircell injurycell typeexperimental studyglucose metabolismhealingimprovedin vivoinhibitor/antagonistinnovationinsightjoint destructionjoint functionjoint injuryjoint loadingjoint mobilizationmechanical forcemechanical loadmechanotransductionmetabolomicsnew therapeutic targetnovelpre-clinicalpre-clinical researchreaction raterepairedrespiratoryresponsesexsmall molecule inhibitortranslational approachviscoelasticity
项目摘要
All cells are subject to and respond to mechanical forces like compression. However the molecular mechanisms
linking the mechanics to biological responses are not fully understood. The cells of our model system, the
chondrocytes of cartilage, undergo compression in vivo, and these cells can transduce compression into
biological signals. There is evidence that glucose utilization in chondrocytes is regulated by compression and
that physiologic compression stimulates glycolysis, the main pathway chondrocytes use to make ATP. This
phenomenon has been linked to the ability of chondrocytes to maintain cartilage. Thus, the study of glucose
metabolism is relevant to NIH because millions suffer from chondrocyte-driven cartilage deterioration in
osteoarthritis. Current osteoarthritis treatments involve joint motion, which is counterintuitive. We show for the
first time that physiologically relevant culture conditions enable in vitro compression of chondrocytes. This
project tests the hypothesis that physiological compression of both normal and osteoarthritic chondrocytes
results in a specific pattern of metabolites within glucose metabolism that support protein production to maintain
the cellular microenvironment. The premise is that by quantifying glucose metabolism in chondrocytes this
project will develop strategies that use mechanical loading to produce the building blocks for cartilage repair.
Aim 1 - In vitro experiments will examine the source of carbon (glucose or glutamine) and the mechanism of
regulation. Dependent variables include sex, donor age and the level (low or high) of applied compression.
Targeted metabolomics data will be generated from normal and osteoarthritic chondrocytes subjected to
compression under different experimental conditions. Aim 2 - Experiments using mice subjected to voluntary
running will assess in vivo mechanotransduction. Dependent variables include sex and the duration of running.
Readouts will include both targeted metabolites and immunohistological markers examining regulation of
glucose metabolism. Assays will employ highly specific enzyme inhibitors that will allow a step-by-step analysis
of critical metabolic pathways. This project has substantial innovation including a novel systems biology model
and analytical approach that calculate the relative rates of reaction for each step in glucose metabolism. These
modeling results will be used both to refine existing hypotheses and to generate new ones. The goal of this
project is to identify changes in patterns of small metabolites that result from compression for normal and
osteoarthritic chondrocytes. The expected outcome is to identify candidate target reactions that leverage
glucose metabolism to increase mechanically driven production of amino acid precursors to repair cartilage.
Understanding these mechanisms may prove useful in developing translational strategies to heal cartilage by
activating existing mechanosensitive pathways. Insight into how chondrocytes respond to compression will
advance osteoarthritis translation by providing new therapeutic targets for cartilage repair and enabling
substantial clinical progress.
所有细胞都会受到机械力(如压缩)的影响并对其做出反应。然而分子机制
机制与生物反应的联系尚未完全了解。我们模型系统的细胞,
软骨的软骨细胞在体内受到压缩,这些细胞可以将压缩转化为
生物信号。有证据表明软骨细胞中的葡萄糖利用受到压缩和调节
生理压力会刺激糖酵解,这是软骨细胞制造 ATP 的主要途径。这
这种现象与软骨细胞维持软骨的能力有关。因此,葡萄糖的研究
新陈代谢与 NIH 相关,因为数百万人遭受软骨细胞驱动的软骨退化
骨关节炎。目前的骨关节炎治疗涉及关节运动,这是违反直觉的。我们展示的是
生理相关的培养条件首次实现了软骨细胞的体外压缩。这
该项目测试了以下假设:正常软骨细胞和骨关节炎软骨细胞的生理压缩
导致葡萄糖代谢中代谢物的特定模式,支持蛋白质生产以维持
细胞微环境。前提是通过量化软骨细胞中的葡萄糖代谢,
该项目将制定使用机械加载来生产软骨修复构件的策略。
目标 1 - 体外实验将检查碳的来源(葡萄糖或谷氨酰胺)及其机制
规定。因变量包括性别、捐献者年龄和施加压缩的水平(低或高)。
将从正常和骨关节炎软骨细胞中产生靶向代谢组学数据
不同实验条件下的压缩。目标 2 - 使用自愿接受实验的小鼠进行实验
跑步将评估体内机械转导。因变量包括性别和跑步持续时间。
读数将包括目标代谢物和免疫组织学标记,检查调节
葡萄糖代谢。检测将采用高度特异性的酶抑制剂,以便进行逐步分析
关键代谢途径。该项目具有重大创新,包括新颖的系统生物学模型
计算葡萄糖代谢每个步骤的相对反应速率的分析方法。这些
建模结果将用于完善现有假设并生成新假设。此举的目标
该项目的目的是确定正常和正常压缩导致的小代谢物模式的变化。
骨关节炎软骨细胞。预期结果是确定候选目标反应,利用
葡萄糖代谢增加机械驱动的氨基酸前体的产生以修复软骨。
了解这些机制可能有助于制定通过以下方式治愈软骨的转化策略:
激活现有的机械敏感途径。深入了解软骨细胞如何响应压缩
通过提供软骨修复的新治疗靶点并促进骨关节炎转化
实质性临床进展。
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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Ronald Kent June其他文献
Ronald Kent June的其他文献
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{{ truncateString('Ronald Kent June', 18)}}的其他基金
Metabolomic Profiling to Identify Candidate Biomarker Profiles and Molecular Endotypes for Osteoarthritis
通过代谢组学分析来鉴定骨关节炎的候选生物标志物谱和分子内型
- 批准号:
10737184 - 财政年份:2023
- 资助金额:
$ 20.74万 - 项目类别:
Role of Glucose metabolism in Chondrocyte Mechanotransduction
葡萄糖代谢在软骨细胞力转导中的作用
- 批准号:
10400393 - 财政年份:2019
- 资助金额:
$ 20.74万 - 项目类别:
Role of Glucose metabolism in Chondrocyte Mechanotransduction
葡萄糖代谢在软骨细胞力转导中的作用
- 批准号:
10405650 - 财政年份:2019
- 资助金额:
$ 20.74万 - 项目类别:
Role of Glucose metabolism in Chondrocyte Mechanotransduction
葡萄糖代谢在软骨细胞力转导中的作用
- 批准号:
10677210 - 财政年份:2019
- 资助金额:
$ 20.74万 - 项目类别:
Role of Glucose metabolism in Chondrocyte Mechanotransduction
葡萄糖代谢在软骨细胞力转导中的作用
- 批准号:
10183168 - 财政年份:2019
- 资助金额:
$ 20.74万 - 项目类别:
Role of Glucose metabolism in Chondrocyte Mechanotransduction
葡萄糖代谢在软骨细胞力转导中的作用
- 批准号:
9924448 - 财政年份:2019
- 资助金额:
$ 20.74万 - 项目类别:
Research Supplements to Promote Re-Entry: Role of Glucose metabolism in Chondrocyte Mechanotransduction
促进重返的研究补充剂:葡萄糖代谢在软骨细胞机械转导中的作用
- 批准号:
10086619 - 财政年份:2019
- 资助金额:
$ 20.74万 - 项目类别:
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为残疾学生提供博士前奖学金
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6803531 - 财政年份:2003
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$ 20.74万 - 项目类别:
PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES
为残疾学生提供博士前奖学金
- 批准号:
7123029 - 财政年份:2003
- 资助金额:
$ 20.74万 - 项目类别:
PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES
为残疾学生提供博士前奖学金
- 批准号:
6941306 - 财政年份:2003
- 资助金额:
$ 20.74万 - 项目类别:
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