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.
所有的细胞都受到机械力的影响,并对机械力做出反应,比如压缩。然而,分子机制
将机制与生物反应联系起来还不完全清楚。我们的模型系统的细胞,
软骨的软骨细胞在体内经历压缩,并且这些细胞可以将压缩成
生物信号有证据表明,软骨细胞中的葡萄糖利用受压缩和
生理压力刺激糖酵解,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有关,因为数百万人患有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。我们展示了
第一次,生理相关的培养条件能够在体外压缩软骨细胞。这
项目测试的假设,生理压缩正常和骨关节炎软骨细胞
导致葡萄糖代谢中特定的代谢物模式,其支持蛋白质产生以维持
细胞微环境。前提是通过量化软骨细胞中的葡萄糖代谢,
该项目将开发使用机械加载来产生软骨修复的构建块的策略。
目的1 -体外实验将检查碳源(葡萄糖或谷氨酰胺)和
调控因变量包括性别、供体年龄和施加的压缩水平(低或高)。
靶向代谢组学数据将从正常和骨关节炎软骨细胞产生,
在不同的实验条件下。目的2 -使用自愿接受免疫治疗的小鼠的实验
跑步将评估体内机械传导。因变量包括性别和跑步的持续时间。
读数将包括靶向代谢物和免疫组织学标记物,检查细胞内的
葡萄糖代谢检测将采用高度特异性的酶抑制剂,允许逐步分析
关键的代谢途径。该项目具有实质性的创新,包括一个新的系统生物学模型
以及计算葡萄糖代谢中每一步反应的相对速率的分析方法。这些
建模结果将用于完善现有假设并产生新的假设。这个目标
该项目是为了确定小代谢物的模式的变化,导致压缩正常和
骨关节炎软骨细胞预期的结果是确定候选目标反应,
葡萄糖代谢,以增加机械驱动的氨基酸前体的产生来修复软骨。
了解这些机制可能有助于开发翻译策略,通过以下方式治愈软骨:
激活现有的机械敏感通路。深入了解软骨细胞对压力的反应将有助于
通过为软骨修复提供新的治疗靶点,
临床上取得了实质性进展。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ronald Kent June其他文献
Ronald Kent June的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
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:
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:
10677210 - 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:
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:
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:
6803531 - 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:
7280944 - 财政年份:2003
- 资助金额:
$ 20.74万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Research Grant