Treatment of inflammation via activation of the mRNA-destabilising protein tristetraprolin

通过激活 mRNA 不稳定蛋白 tristetraprolin 治疗炎症

• 批准号: MR/S002871/1
• 负责人: Andrew Clark
• 金额: $ 98.28万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS002871%2F1
• 关键词: Treatment; inflammation; via; activation; mRNA

Inflammation is a healthy response to infection or physical damage, which helps to eliminate harmful microbes. However, many of the factors released during an inflammatory response cannot discriminate between self and microbe, and therefore risk causing collateral damage to the inflamed tissue. For this reason, inflammation is usually very tightly regulated. A healthy inflammatory response has a rapid onset and an orderly resolution phase, in which activated immune cells exit the inflamed tissue or return to their resting state. This allows normal function of the affected tissue to be restored with minimal damage. An inflammatory trigger can be thought of as an accelerator pedal, and resolution as the brake: safe driving requires judicious use of both.Inadequately controlled, damaging inflammation is the defining characteristic of chronic diseases like rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease and many others. Uncontrolled inflammation also strongly contributes to cardiovascular disease, neurodegenerative conditions like Alzheimer's disease, and many forms of cancer. For decades the main focus of researchers on these diseases has been to identify triggers of inflammation and try to block their effects. This approach has met with only moderate success, and the overall economic, societal and personal burdens of chronic inflammatory disease continue to grow in the developed world. The focus on triggers of inflammation risks overlooking the equally important process of resolution. Evidence both from genetic studies of human disease and from animal experiments clearly shows that inflammatory disease can be caused or made worse by defects in the "braking" mechanisms that underlie resolution. More and more researchers are now trying to understand the biological processes involved in the resolution of inflammation. It is thought that reinforcement of resolution mechanisms may be an effective way to treat inflammatory diseases.Our research on a protein called tristetraprolin (TTP) develops the concept of reinforcing resolution. Mice that cannot produce TTP develop severe, spontaneous inflammatory disease, therefore we know that TTP is an important brake to inflammation. We have also learned that the function of TTP is controlled by a molecular switch that converts it between active and inactive states. We can detect a lot of TTP protein in chronically inflamed joints of patients with rheumatoid arthritis, but it seems to be in the inactive state. We suspect that the persistent inactivation of TTP prevents resolution of inflammation, much like a faulty brake. We believe it will be possible to reduce inflammation by restoring the function of TTP, effectively repairing the damaged brake. To do this, we plan to use two different drugs that we predict will switch TTP from inactive to active state. One of these drugs is already used to treat multiple sclerosis, whilst the other is being investigated as a potential treatment for cancer. If this work is successful it may lead to new clinical trials, and ultimately to an entirely new type of treatment for inflammatory diseases, one that is based on promoting resolution rather than blocking inflammatory triggers.

炎症是对感染或身体损害的健康反应，这有助于消除有害的微生物。但是，在炎症反应期间释放的许多因素无法区分自我和微生物，因此可能会对发炎组织造成附带损害。因此，炎症通常受到非常严格的调节。健康的炎症反应具有迅速的发作和有序的分辨率阶段，其中活化的免疫细胞退出了发炎的组织或恢复其静止状态。这允许受影响组织的正常功能通过最小的损害恢复。炎症触发因素可以被认为是加速踏板，而作为制动器的解决方案：安全驾驶需要明智地使用两者。受到控制，受损的炎症是类风湿关节炎，慢性阻塞性肺部疾病，炎症性肠疾病等慢性疾病的定义特征。不受控制的炎症也有很大的促进，导致心血管疾病，神经退行性疾病（如阿尔茨海默氏病）和多种形式的癌症。几十年来，研究人员对这些疾病的主要重点一直是识别炎症的触发因素并试图阻止其影响。这种方法仅取得了适度的成功，并且在发达国家的慢性炎症性疾病的总体经济，社会和个人负担继续增长。对炎症触发的关注风险忽略了同样重要的解决过程。来自人类疾病的遗传研究和动物实验的证据清楚地表明，通过解决基础的“制动”机制的缺陷可能会引起或使炎症性疾病变得更糟。现在，越来越多的研究人员试图了解炎症解决方案所涉及的生物学过程。人们认为，加强分辨率机制可能是治疗炎症性疾病的有效方法。我们对一种称为三烷二帕林（TTP）的蛋白质的研究发展了加强分辨率的概念。无法产生TTP的小鼠会出现严重的自发性炎症性疾病，因此我们知道TTP是炎症的重要制动器。我们还了解到，TTP的功能受到分子开关的控制，该分子开关将其转换在活动状态和非活动状态之间。我们可以在类风湿关节炎患者的慢性发炎关节中检测到许多TTP蛋白，但似乎处于不活跃状态。我们怀疑TTP的持续失活阻止了炎症的分辨率，就像有故障的制动器一样。我们认为，可以通过恢复TTP的功能来减少炎症，从而有效地修复受损的制动器。为此，我们计划使用两种不同的药物，我们预计将将TTP从非活动状态转换为活跃状态。其中一种药物之一已用于治疗多发性硬化症，而另一种药物则被研究为对癌症的潜在治疗方法。如果这项工作成功，它可能会导致新的临床试验，并最终导致一种全新的炎症性疾病治疗方法，该治疗方法基于促进分辨率而不是阻止炎症触发因素。