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)是全球残疾的主要原因,对女性的影响尤其严重。理解
驱动年龄和性别特异性软骨退化的精确机制将大大增加我们的
对OA发病机制的基本了解,并导致新疾病的发展,
治疗最近的证据已经确定了核定位的脱乙酰酶,sirtuin 6(SIRT 6),作为一个主
调节衰老过程,部分通过促进抗氧化应激。在小鼠中,SIRT 6
过度表达延长寿命,但仅在男性中,这提出了有趣的可能性,性别特异性
SIRT 6功能的差异可以调节驱动OA的年龄相关机制。我们的初步数据,
软骨细胞表明SIRT 6活性随着年龄的增长而下降,导致SIRT 6水平的显著增加。
硫氧还蛋白(Trx)相互作用蛋白(TXNIP)。我们认为增加TXNIP水平
通过结合并抑制抗氧化蛋白硫氧还蛋白(Trx)来加剧氧化应激状况。一
Trx的主要功能是通过直接抑制凋亡信号来抑制分解代谢氧化还原信号传导事件
调节激酶(ASK 1)。我们之前已经证明,ASK 1信号可以防止软骨退化,
导致软骨细胞变性和年龄相关的OA。因此,我们的中心假设是,
用SIRT 6激活剂处理的软骨细胞将被保护免受氧化应激和分解代谢信号事件
导致软骨损伤和骨关节炎。目的1将评估是否用小分子活化SIRT 6
激活剂MDL-800可以减轻核特异性氧化应激,其将使用
创新的NLS-Hyper-DAAO氧化还原生物传感器在来自年轻和老年软骨供体的软骨细胞中的应用。
为了确定SIRT 6的作用是否是性别特异性的,两个目的都将使用从男性和女性分离的软骨细胞。
女性人类软骨细胞。为了评估SIRT 6是否直接减弱氧化应激诱导的软骨细胞
损伤,我们将评估:1)氧化还原相关的基因转录,2)抗氧化剂水平,3)DNA损伤和端粒
功能障碍,和4)转录因子活性。实验将在两个大气(21%)
和缺氧(2%)条件下,以确定这些过程中的O2的贡献。在目标2中,执行相同
在目标1中描述的实验中,我们将确定SIRT 6激活如何调节氧化应激信号传导。
软骨细胞通过SIRT 6/TXNIP/Trx/ASK 1轴。为了评估这一点,我们将检查:1)TXNIP-Trx和Trx-
ASK 1复合物形成,2)ASK 1和MAP激酶激活,3)基质降解酶的基因表达。
该项目的结果将确定软骨细胞老化与OA发病机制的具体机制,
可能提供重要的证据,说明为什么这种疾病对妇女的影响更高。它还将提供
未来R 01应用的初步数据,旨在确定如何在体内利用SIRT 6激活
作为减缓或预防OA进展的疗法。最终,我们希望这项工作能够催化
新的疾病修饰治疗,将减少与年龄和OA相关的身体困难。
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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