Musculoskeletal tissues ageing: the role of microRNAs and joints homeostasis

肌肉骨骼组织衰老：microRNA 和关节稳态的作用

• 批准号: 2106124
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2106124
• 关键词: Musculoskeletal; tissues; ageing; role; microRNAs

The societal impact of musculoskeletal (MSK) disorders is increasing as the number of older people is predicted to reach over 60 million (in UK) by 2020. It is therefore essential to determine the mechanisms underlying age-related functional deterioration of MSK tissues. It is likely that deterioration of the individual MSK tissue may depend on the state of the other MSK tissues, eg joint degeneration may be affected by muscle weakness. The molecular mechanisms governing MSK ageing are still not understood, however epigenetic mechanisms are thought to play key roles.microRNAs (miRs), robust regulators of gene expression, affect the functionality of most tissues and provide a high-throughput response mechanism to ageing and environmental changes (Brown & Goljanek-Whysall, 2015). Differential expression of miRs in muscle, bone and cartilage has been described during ageing, however the relevance of this is not fully understood (Soriano, 2016; Steinbush, 2017).Our data shows changes in the expression of several miRs: miR-24, miR-128 and miR-34, and their targets in MSK tissues of old mice. These miRs have been shown or are predicted to target fundamental genes for MSK tissue homeostasis: extracellular matrix genes and TGFB signalling. We have also shown that regulation of miR expression improves muscle mass and strength in old mice (man in prep). Although limited, our data indicates the involvement of miRs in driving osteoarthritis-like changes during ageing. Specifically, we have shown that miR-199 dysregulation in cartilage of old mice are associated with cartilage degeneration; this can be modulated using intraarticular injections of miR-199 mimic/antagomiR in the loading model of osteoarthritis (Poulet, 2011).The overall aim of this project is to establish whether disrupted miR:target interactions affect MSK tissue ageing and whether miR-based intervention has the potential to ameliorate age-related MSK dysfunction associated with muscle wasting and OA-like symptoms. Specifically, we will:1. Validate expression of selected miRs and their predicted targets in skeletal muscle, cartilage, bone during ageing.2. Investigate miR:target regulatory network(s) in vitro and in vivo using established miR gain- and loss-of-function approaches and target gene reporters.3. Establish the effects of interventions in vitro and in vivo on miR:target interactions on musculoskeletal tissue homeostasis during ageing.

肌肉骨骼（MSK）疾病的社会影响正在增加，因为预计到2020年老年人的数量将超过6000万（在英国）。因此，有必要确定MSK组织与年龄相关的功能恶化的机制。单个MSK组织的恶化可能取决于其他MSK组织的状态，例如关节退行性变可能受到肌肉无力的影响。控制MSK衰老的分子机制仍不清楚，但表观遗传机制被认为起着关键作用。microRNA（miR）是基因表达的强大调节因子，影响大多数组织的功能，并为衰老和环境变化提供高通量响应机制（Brown & Goljanek-Whysall，2015）。人们已经描述了衰老过程中肌肉、骨骼和软骨中miR的差异表达，但其相关性尚未完全了解（Soriano，2016; Steinbush，2017）。我们的数据显示了几种miR表达的变化：miR-24、miR-128和miR-34，以及它们在老年小鼠MK组织中的靶点。这些miR已经显示或预测靶向MSK组织稳态的基础基因：细胞外基质基因和TGFB信号传导。我们还表明，调节miR表达可以改善老年小鼠的肌肉质量和力量。虽然有限，但我们的数据表明miR参与驱动衰老过程中的骨关节炎样变化。具体地说，我们已经表明，老年小鼠软骨中的miR-199失调与软骨变性有关;这可以通过在骨关节炎负荷模型中关节内注射miR-199模拟物/miR-199受体来调节。（Poulet，2011）。该项目的总体目标是确定是否破坏miR：靶向相互作用影响MSK组织衰老，以及基于miR的干预是否有可能改善衰老，与肌肉萎缩和OA样症状相关的MSK功能障碍。具体来说，我们将：1。研究所选miRs及其预测靶点在骨骼肌、软骨、骨衰老过程中的表达.使用已建立的miR功能获得和功能丧失方法和靶基因阻断剂在体外和体内研究miR：靶调控网络。建立体外和体内干预对衰老过程中肌肉骨骼组织稳态的miR：靶标相互作用的影响。