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伤的健康反应，有助于消除有害微生物。然而，炎症反应过程中释放的许多因子无法区分自身和微生物，因此有可能对发炎组织造成附带损害。因此，炎症通常受到非常严格的控制。健康的炎症反应具有快速发作和有序消退阶段，其中激活的免疫细胞离开发炎组织或返回到其静息状态。这使得受影响组织的正常功能能够以最小的损伤恢复。炎症触发因素可以被认为是加速踏板，而解决方案则可以被认为是刹车：安全驾驶需要明智地使用两者。控制不当、破坏性炎症是类风湿性关节炎、慢性阻塞性肺病、炎症性肠病等慢性疾病的决定性特征还有许多其他人。不受控制的炎症也会导致心血管疾病、阿尔茨海默病等神经退行性疾病以及多种癌症。几十年来，研究人员对这些疾病的主要关注点一直是确定炎症的诱因并试图阻止其影响。这种方法只取得了一定的成功，慢性炎症性疾病的总体经济、社会和个人负担在发达国家继续增加。关注炎症的触发因素可能会忽视同样重要的消退过程。来自人类疾病遗传学研究和动物实验的证据清楚地表明，炎症性疾病可能是由解决问题的“刹车”机制的缺陷引起或恶化。现在越来越多的研究人员试图了解炎症消退所涉及的生物过程。人们认为，强化分解机制可能是治疗炎症性疾病的有效方法。我们对一种名为三四脯氨酸（TTP）的蛋白质的研究提出了强化分解的概念。不能产生 TTP 的小鼠会出现严重的自发炎症性疾病，因此我们知道 TTP 是炎症的重要抑制因素。我们还了解到，TTP 的功能是由分子开关控制的，分子开关可将其在活性和非活性状态之间转换。我们可以在类风湿关节炎患者的慢性发炎关节中检测到大量的TTP蛋白，但它似乎处于不活跃状态。我们怀疑 TTP 的持续失活会阻碍炎症的消退，就像刹车失灵一样。我们相信通过恢复TTP的功能来减少炎症，有效修复受损的刹车是可能的。为此，我们计划使用两种不同的药物，我们预测它们会将 TTP 从非活性状态转变为活性状态。其中一种药物已用于治疗多发性硬化症，而另一种药物正在研究作为癌症的潜在治疗方法。如果这项工作成功，可能会导致新的临床试验，并最终产生一种全新的炎症性疾病治疗方法，这种治疗方法的基础是促进消退而不是阻断炎症触发因素。

项目成果

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration.

蛋白磷酸酶 2A 作为炎症和神经退行性疾病的治疗靶点。

• DOI: http://dx.10.1016/j.pharmthera.2019.05.016
• 发表时间: 2019
• 期刊: Pharmacology & therapeutics
• 影响因子: 13.5
• 作者: Clark AR

The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3.

TTP 磷酸化在 MK2/3 调节炎症细胞因子产生中的作用。

• DOI: http://dx.10.4049/jimmunol.1801221
• 发表时间: 2019
• 期刊: 1950)
• 作者: Ronkina N