SIRT6 as a novel therapeutic target in aging and age-related osteoarthritis
SIRT6 作为衰老和年龄相关骨关节炎的新型治疗靶点
基本信息
- 批准号:10303788
- 负责人:
- 金额:$ 7.8万
- 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:2021-09-30 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAffectAgeAgingAntioxidantsApoptosisAttenuatedBindingBiosensorCartilageChondrocytesChromatinCo-ImmunoprecipitationsComplexDNA DamageDataDeacetylaseDegenerative polyarthritisDevelopmentDiseaseEnzymesEventFunctional disorderFutureGene ExpressionGenesGenetic TranscriptionGoalsHomeostasisHumanHydrogen PeroxideHypoxiaJointsKnock-outLeadLinkLongevityMAPK8 geneMaintenanceMeasuresMediatingMetabolicMetabolic dysfunctionMetalloproteasesMissionMitogen-Activated Protein KinasesMolecularMusNuclearObese MiceOxidation-ReductionOxidative StressPathogenesisPathologyPathway interactionsPhosphorylationPhosphotransferasesPreventive therapyProcessPromoter RegionsProteinsPublic HealthReactive Oxygen SpeciesReporterRepressionResistanceReverse Transcriptase Polymerase Chain ReactionRoleSex DifferencesSignal PathwaySignal TransductionSirtuinsSystemTXN geneTXNIP geneTherapeutic InterventionThioredoxin-2TissuesWomanWorkage relatedagedaggrecanasecartilage degradationcatalystchromatin immunoprecipitationclinical developmentclinically relevantdefined contributiondisabilityexperimental studyhealthspanhealthy aginghuman femalehuman maleimprovedin vivoinnovationjoint destructionmalemouse modelnew therapeutic targetoverexpressionoxidative damagep38 Mitogen Activated Protein Kinasepreventsexsmall moleculesystemic inflammatory responsetelomeretooltranscription factor
项目摘要
Osteoarthritis (OA) is a leading cause of global disability, and disproportionally affects women. Understanding
the precise mechanisms that drive age and sex-specific cartilage degeneration would greatly increase our
fundamental understanding of OA pathogenesis and lead to the development of new disease modifying
therapies. Recent evidence has identified the nuclear localized deacetylase, sirtuin 6 (SIRT6), as a master
regulator of aging processes, in part through promoting resistance to oxidative stress. In mice, SIRT6
overexpression extends lifespan, but only in males, which raises the intriguing possibility that sex specific
differences in SIRT6 function could regulate age-associated mechanisms that drive OA. Our preliminary data in
chondrocytes demonstrates that SIRT6 activity declines with age, resulting in a significant increase in the levels
of the pro-oxidant, thioredoxin (Trx) interacting protein (TXNIP). We propose that increasing levels of TXNIP
exacerbate oxidative stress conditions by binding to, and inhibiting, the antioxidant protein, thioredoxin (Trx). A
major function of Trx is to suppress catabolic redox signaling events through direct repression of apoptosis signal
regulating kinase (ASK1). We have previously shown that ASK1 signaling prevents cartilage degeneration and
leads to chondrocyte degeneration and age-associated OA. Thus, our central hypothesis is that aged
chondrocytes treated with a SIRT6 activator will be protected from oxidative stress and catabolic signaling events
that drive cartilage damage and promote OA. Aim 1 will assess if activation of SIRT6 with the small molecule
activator, MDL-800, can mitigate nuclear-specific oxidative stress that will be generated and measured using the
innovative NLS-HyPer-DAAO redox biosensor in chondrocytes derived from younger and older cartilage donors.
To determine if the effects of SIRT6 are sex-specific, both Aims will use chondrocytes isolated from male and
female human chondrocytes. To assess if SIRT6 directly attenuates oxidative stress induced chondrocyte
damage, we will assess: 1) redox-related gene transcription, 2) antioxidant levels, 3) DNA damage and telomere
dysfunction, and 4) transcription factor activity. Experiments will be conducted under both atmospheric (21%)
and hypoxic (2%) conditions to define the contribution of O2 on these processes. In Aim 2, performing the same
experiments described in Aim 1, we will determine how SIRT6 activation modulates oxidative stress signaling in
chondrocytes through the SIRT6/TXNIP/Trx/ASK1 axis. To assess this, we will examine: 1) TXNIP-Trx and Trx-
ASK1 complex formation, 2) ASK1 and MAP kinase activation, 3) gene expression of matrix degrading enzymes.
Results from this project will define the specific mechanisms linking chondrocyte aging to OA pathogenesis and
may provide significant evidence as to why this disease effects women at a higher rate. It will also provide
preliminary data for a future R01 application aimed at determining how SIRT6 activation can be utilized in vivo
as a therapy to slow or prevent the progression of OA. Ultimately, we expect this work to catalyze the discovery
of new disease-modifying treatments that will reduce the physical hardships associated with age and OA.
骨关节炎(OA)是全球致残的主要原因,对女性的影响尤为严重。理解
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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John A Collins其他文献
Cartilage-specific emSirt6/em deficiency represses IGF-1 and enhances osteoarthritis severity in mice
软骨特异性 emSirt6/em 缺乏抑制胰岛素样生长因子 1 并加重小鼠骨关节炎的严重程度
- DOI:
10.1136/ard-2023-224385 - 发表时间:
2023-11-01 - 期刊:
- 影响因子:20.600
- 作者:
John A Collins;C James Kim;Ashley Coleman;Abreah Little;Matheus M Perez;Emily J Clarke;Brian Diekman;Mandy J Peffers;Susanna Chubinskaya;Ryan E Tomlinson;Theresa A Freeman;Richard F Loeser - 通讯作者:
Richard F Loeser
John A Collins的其他文献
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