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.

项目摘要/摘要 年龄是骨关节炎（OA）的头号危险因素，但是，与年龄相关的机制 关节变化以及这些造成软骨损伤的贡献的定义不当。随着OA关节组织的年龄，它是 很好地确定，软骨形成干细胞（CSC）的能力显着下降 区分，联合环境变得更加炎症。这两个因素一起破坏了 从伤害中恢复的能力以及自体干细胞疗法的失败。因此，我们 提出一种创新的双重策略，可以解决这两者。我们假设Sirtuin 6（SIRT6）的激活 将恢复较旧的CSC，调节激酶1（ASK1）抑制的凋亡信号将重新建立A 关节的再生环境。这种新颖的解决方案在一起有可能大大提高能力 用于CSC分化和软骨修复。我们将检验这一假设，并确定 SIRT6在以下三个目标中调节SIRT6的表观遗传机制。在AIM 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的生存活动。在AIM 2中，我们将确定SIRT6激活的功效 存在Ask1抑制作用以刺激老年，雄性和雌性啮齿动物的软骨形成。最后，在AIM 3中 我们将确定SIRT6激活和ASK1抑制的功效，以促进软骨再生和 响应于临床前陈年的米蒂格模型中的软骨损伤修复。这些目标将通过 概念验证证明，全面对年轻人和年轻人（男性和女性）CSC和巨噬细胞的体外分析 老化的啮齿动物模型（小鼠和大鼠），以及临床上相关的大动物软骨缺陷模型（年龄Minipig）。 重要的是，该提案的发现可能会给您独特而重要的见解 老化细胞的表观遗传调节以及周围环境在其他衰老和患病中的作用 组织。如果成功，这种新颖的促进疗法的总体影响可以改善衰老的破坏 和关节伤害将代表与年龄相关疾病的治疗方面的重大进步，例如 OA。此外，这将导致发现其他器官系统和 提高老年人群过着健康的移动生活的能力。