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.

项目概要/摘要 年龄是骨关节炎 (OA) 的第一大危险因素，然而，驱动年龄相关的机制 关节变化以及这些变化如何导致软骨损伤尚不清楚。随着 OA 关节组织的老化， 众所周知，软骨形成干细胞 (CSC) 的能力显着下降 分化，关节环境变得更加炎症。这两个因素共同破坏了 从损伤中恢复的能力也导致自体干细胞疗法的失败。因此，我们 提出一项创新的双重战略来解决这两个问题。我们假设 Sirtuin 6 (SIRT6) 的激活 将使较老的 CSC 恢复活力，并且抑制凋亡信号调节激酶 1 (ASK1) 将重新建立 关节内的再生环境。总之，这种新颖的解决方案有可能大大增强能力 用于老年人群中的 CSC 分化和软骨修复。我们将检验这个假设并确定 SIRT6 在以下三个目标中调节表观遗传机制。在目标 1 中，我们将确定 (a) SIRT6 激活和 (b) ASK1 抑制增强软骨形成分化的机制 和老年 CSC 的促生存活动。在目标 2 中，我们将确定 SIRT6 激活的功效， ASK1 抑制的存在可刺激老年、雄性和雌性啮齿动物的软骨形成。最后，在目标 3 中， 我们将确定 SIRT6 激活和 ASK1 抑制对促进软骨再生和 在临床前老年小型猪模型中修复软骨损伤。这些目标将通过以下方式实现 在概念验证中对年轻人和老年人（男性和女性）CSC 和巨噬细胞进行全面的体外分析 衰老啮齿动物模型（小鼠和大鼠），以及临床相关的大型动物软骨缺损模型（老年小型猪）。 重要的是，该提案的研究结果可能会对以下方面的作用提供独特而重要的见解： 衰老细胞的表观遗传调控以及周围环境在其他衰老和疾病中的作用 组织。如果成功的话，这种新型促再生疗法对减轻衰老破坏的总体影响 关节损伤将代表与年龄相关的疾病治疗的重大进步，例如 办公自动化。此外，它将导致发现其他器官系统和疾病的新治疗方法 提高老年人口健康、流动生活的能力。