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

• 批准号: 10303788
• 负责人: John A Collins
• 金额: $ 7.8万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10303788
• 关键词: Acceleration; Affect; Age; Aging; Antioxidants; Apoptosis; Attenuated; Binding; Biosensor; Cartilage; Chondrocytes; Chromatin; Co-Immunoprecipitations; Complex; DNA Damage; Data; Deacetylase; Degenerative polyarthritis; Development; Disease; Enzymes; Event; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Goals; Homeostasis; Human; Hydrogen Peroxide; Hypoxia; Joints; Knock-out; Lead; Link; Longevity; MAPK8 gene; Maintenance; Measures; Mediating; Metabolic; Metabolic dysfunction; Metalloproteases; Mission; Mitogen-Activated Protein Kinases; Molecular; Mus; Nuclear; Obese Mice; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Preventive therapy; Process; Promoter Regions; Proteins; Public Health; Reactive Oxygen Species; Reporter; Repression; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sex Differences; Signal Pathway; Signal Transduction; Sirtuins; System; TXN gene; TXNIP gene; Therapeutic Intervention; Thioredoxin-2; Tissues; Woman; Work; age related; aged; aggrecanase; cartilage degradation; catalyst; chromatin immunoprecipitation; clinical development; clinically relevant; defined contribution; disability; experimental study; healthspan; healthy aging; human female; human male; improved; in vivo; innovation; joint destruction; male; mouse model; new therapeutic target; overexpression; oxidative damage; p38 Mitogen Activated Protein Kinase; prevent; sex; small molecule; systemic inflammatory response; telomere; tool; transcription factor

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