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/摘要 年龄是骨关节炎（OA）的头号危险因素，然而，驱动年龄相关性骨关节炎的机制， 关节的变化以及这些变化如何导致软骨损伤还没有很好的定义。随着OA关节组织的老化， 软骨形成干细胞（CSCs）显示出它们的能力显着下降， 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，也导致自体干细胞治疗的失败。因此我们 提出一项创新的双重战略，解决这两个问题。我们假设沉默调节蛋白6（SIRT 6）的激活 细胞凋亡信号调节激酶1（ASK 1）的抑制将重新建立一个新的细胞周期。 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 用于老年人群中的CSC分化和软骨修复我们将测试这一假设，并确定 SIRT 6在以下三个目的中调节的表观遗传机制。在目标1中，我们将确定 （a）SIRT 6激活和（B）ASK 1抑制增强软骨形成分化的机制 和促存活活性。在目标2中，我们将确定SIRT 6激活在以下情况中的功效： ASK 1抑制的存在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SIRT 6激活和ASK 1抑制促进软骨再生的功效， 在临床前老龄小型猪模型中，这些目标将通过 在概念验证中，对年轻和老年（男性和女性）CSC和巨噬细胞进行全面的体外分析 老化啮齿动物模型（小鼠和大鼠）和临床相关的大型动物软骨缺损模型（老化小型猪）。 重要的是，这项提案的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节以及周围环境在其他衰老和疾病中的作用 组织中如果成功，这种新型促再生疗法对改善衰老破坏的总体影响 和关节损伤将代表治疗年龄相关疾病的重大进展， OA。此外，它将导致发现新的疾病修饰治疗其他器官系统， 提高老年人过上健康的、移动的生活的能力。