Promoting regenerative repair of aged cartilage

促进老化软骨的再生修复

• 批准号: 10660184
• 负责人: John A Collins
• 金额: $ 73.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660184
• 关键词: 3-Dimensional; Address; Age; Aging; Animal Model; Animals; Anti-Inflammatory Agents; Autologous; Cartilage; Cell Death; Cells; Chondrocytes; Chondrogenesis; Coculture Techniques; Data; Defect; Degenerative polyarthritis; Disease; Disease Progression; Environment; Epigenetic Process; Event; Failure; Family suidae; Female; Genes; Genetic; Histology; Hydrogels; Immune; In Vitro; Inflammation; Inflammatory; Inhibition of Apoptosis; Injections; Injury; Intervention; Joints; Life; MAP3K5 gene; Macrophage; Miniature Swine; Modeling; Mus; Oral; Osteogenesis; Oxidative Stress; Persons; Probability; Production; Proliferating; Proteins; Publishing; Rattus; Rejuvenation; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Sirtuins; Site; Spectroscopy, Fourier Transform Infrared; Testing; Thick; Tissues; adult stem cell; aged; aging population; anti aging; articular cartilage; body system; cartilage degradation; cartilage regeneration; cartilage repair; cell age; cell motility; clinical translation; clinically relevant; cytokine; efficacy evaluation; epigenetic regulation; exhaustion; healing; in vivo; inhibitor; innovation; insight; joint injury; male; matrigel; microCT; novel; novel strategies; pharmacologic; pre-clinical; prevent; regenerative; regenerative repair; regenerative therapy; regenerative tissue; repaired; response; stem cell differentiation; stem cell population; stem cell therapy; stem cells; stress kinase; tissue culture; translational potential

PROJECT SUMMARY/ABSTRACT Age is the number one risk factor for osteoarthritis (OA), however, the mechanisms that drive age-associated joint changes and how these contribute to cartilage damage are not well defined. As OA joint tissues age, it is well established that cartilage-forming stem cells (CSCs) display a significant decline in their ability to differentiate, and the joint environment becomes more inflammatory. Both of these factors together undermine the ability to recover from injuries and also contributes to the failure of autologous stem cell therapies. Thus, we propose an innovative dual strategy which will address both. We hypothesize that activation of sirtuin 6 (SIRT6) will rejuvenate older CSCs, and apoptosis signal regulating kinase 1 (ASK1) inhibition will reestablish a regenerative environment in the joint. Together, this novel solution has the potential to greatly augment the ability for CSC differentiation and cartilage repair in the aged population. We will test this hypothesis and determine the epigenetic mechanisms that SIRT6 regulate in the following three Aims. In Aim 1, we will determine the mechanisms by which (a) SIRT6 activation and (b) ASK1 inhibition enhance the cartilage-forming differentiation and pro-survival activities of aged CSCs. In Aim 2, we will determine the efficacy of SIRT6 activation, in the presence of ASK1 inhibition to stimulate cartilage formation in aged, male and female rodents. Finally, in Aim 3, we will determine the efficacy of SIRT6 activation and ASK1 inhibition to promote cartilage regeneration and repair in response to chondral injury in a pre-clinical aged minipig model. These Aims will be achieved through comprehensive in vitro analysis of young and old (male and female) CSCs and macrophages, in proof-of-concept aging rodent models (mice and rats), and a clinically relevant large animal chondral defect model (aged minipig). Importantly, the findings from this proposal are likely to give unique and important insights into the role of epigenetic regulation of aged cells and the role of the surrounding environment in other aging and diseased tissues. If successful, the overall impact of this novel pro-regenerative therapy to ameliorate the ravages of aging and joint injury would represent a significant advancement in the treatment of age-associated diseases, such as OA. Additionally, it will lead to the discovery of new disease-modifying treatments for other organ systems and increase the ability of the aged population to live a healthy, mobile life.

项目总结/文摘