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The role of cell senescence in the age-related dysregulation of proteostasis in tendon

细胞衰老在与年龄相关的肌腱蛋白质稳态失调中的作用

基本信息

批准号：
BB/W007282/1
负责人：
Chavaunne Thorpe
金额：
$ 70.4万
依托单位：
Royal Veterinary College
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FW007282%2F1
关键词：
role cell senescence age related

项目摘要

Tendons connect muscles to bone and are essential for movement. They stretch and recoil as we walk and run, improving the efficiency of our movements. Even taking a few steps without the Achilles tendon connecting our calf muscle to our heel would be very difficult. Unfortunately tendons are regularly injured, not only in athletes, but also during normal every day activities, particularly as we get older. Injuries are painful and can be highly limiting, preventing usual activity and decreasing quality of life. They cost the economy millions of pounds every year, not only in treatment costs, but also due to the indirect costs of both work absence and reduced health due to an inability to exercise. Horses also often suffer from tendon injuries, and provide an excellent model in which to study tendon ageing. The risk and characteristics of tendon injury are very similar between humans and horses, and tendons can easily be obtained from young and old horses that are put to sleep for reasons other than tendon injury.Tendon injuries in both humans and horses are difficult to treat, due to a poor understanding of the underlying causes of the age-related decrease in tendon function that leads to increased risk of injury. In other tissues within the body, a common cause of age-related diseases is disruption of the balance between the synthesis and breakdown of proteins that make up the tissue. This process is known as proteostasis, and must be carefully regulated to maintain tissue health. As a tissue ages, its resident cells often lose their ability to grow and divide, and also begin to produce molecules than can cause protein breakdown. These cells are referred to as senescent cells, and cell senescence can disrupt the balance between protein synthesis and breakdown within a tissue. This can reduce the tissue's ability to function properly, which may eventually lead to injury. In this study, we will investigate the relationship between proteostasis and cell senescence in tendon with ageing. First, we will establish how proteostasis alters with ageing in different regions of the horse forelimb superficial digital flexor tendon (SDFT). We will then identify the location of the senescent cells within the SDFT from aged horses, and develop methods to isolate these cells from tendons so we can study them in the laboratory. Using these isolated cells, we will establish how protein synthesis and breakdown changes when the cells become senescent. Finally, we will determine if reversal of senescence by treating the cells with small molecules can restore the balance between protein synthesis and breakdown.The results of this study will allow us to understand, for the first time, the link between cell senescence and proteostasis in tendon. By establishing the effect of reversing tendon cell senescence on protein synthesis and breakdown, we may discover new therapies that can be used to prevent and treat age-related tendon injuries in the future, both in humans and horses.

肌腱连接肌肉和骨骼，是运动所必需的。它们在我们行走和奔跑时伸展和后退，提高了我们运动的效率。即使走几步没有跟腱连接我们的小腿肌肉到我们的脚后跟将是非常困难的。不幸的是，肌腱经常受伤，不仅是运动员，在正常的日常活动中也是如此，特别是随着我们年龄的增长。受伤是痛苦的，可能是高度受限的，阻碍了正常的活动，降低了生活质量。它们每年给英国经济造成数百万英镑的损失，不仅是治疗费用，还因为缺勤和由于无法锻炼而导致的健康下降的间接成本。马也经常遭受肌腱损伤，为研究肌腱老化提供了一个很好的模型。人和马的肌腱损伤的风险和特征非常相似，而且由于肌腱损伤以外的原因而被睡眠的年轻和老年马很容易获得肌腱。人和马的肌腱损伤都很难治疗，因为对导致损伤风险增加的与年龄相关的肌腱功能下降的根本原因缺乏了解。在身体内的其他组织中，与年龄相关的疾病的一个常见原因是组成组织的蛋白质合成和分解之间的平衡被破坏。这一过程被称为蛋白质平衡，必须仔细调节才能维持组织健康。随着组织的老化，其常驻细胞通常会失去生长和分裂的能力，并开始产生能够导致蛋白质分解的分子。这些细胞被称为衰老细胞，细胞衰老会破坏组织内蛋白质合成和分解之间的平衡。这可能会降低组织正常运作的能力，最终可能会导致受伤。在这项研究中，我们将探讨蛋白质平衡和肌腱细胞衰老与衰老的关系。首先，我们将确定在马的前肢浅指屈肌腱(SDFT)的不同区域，蛋白平衡如何随着年龄的增长而改变。然后，我们将确定衰老细胞在老年马的SDFT中的位置，并开发从肌腱中分离这些细胞的方法，以便我们可以在实验室进行研究。利用这些分离的细胞，我们将确定当细胞衰老时蛋白质的合成和分解是如何变化的。最后，我们将确定用小分子处理细胞来逆转衰老是否可以恢复蛋白质合成和分解之间的平衡。这项研究的结果将使我们第一次了解细胞衰老和肌腱蛋白稳态之间的联系。通过建立逆转肌腱细胞衰老对蛋白质合成和分解的影响，我们可能会发现新的治疗方法，在未来可以用于预防和治疗与年龄相关的肌腱损伤，无论是在人还是马身上。