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，在炎症反应期间释放的许多因子不能区分自身和微生物，因此有可能对发炎组织造成附带损害。出于这个原因，炎症通常受到非常严格的调节。健康的炎症反应有一个快速的开始和有序的消退阶段，在这个阶段中，激活的免疫细胞离开炎症组织或返回到它们的静息状态。这允许受影响组织的正常功能以最小的损伤恢复。炎症触发器可以被认为是油门踏板，而解决方案则是刹车：安全驾驶需要明智地使用两者。控制不当，破坏性炎症是慢性疾病的定义特征，如类风湿性关节炎，慢性阻塞性肺病，炎症性肠病和许多其他疾病。不受控制的炎症也会导致心血管疾病，神经退行性疾病，如阿尔茨海默病和许多形式的癌症。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触发因素，并试图阻止它们的影响。这种方法只取得了一定的成功，在发达国家，慢性炎症性疾病的总体经济、社会和个人负担继续增长。对炎症触发因素的关注有可能忽视同样重要的解决过程。人类疾病的遗传学研究和动物实验的证据都清楚地表明，炎症性疾病可能是由作为解决办法基础的“制动”机制的缺陷引起或恶化的。越来越多的研究人员现在正试图了解炎症消退所涉及的生物学过程。增强消退机制被认为是治疗炎症性疾病的有效方法，我们对一种名为tristetraprolin（TTP）的蛋白质的研究发展了增强消退的概念。不能产生TTP的小鼠发展为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的功能是由一个分子开关控制的，该开关将其在活性和非活性状态之间转换。在类风湿关节炎患者的慢性炎症关节中可以检测到大量的TTP蛋白，但它似乎处于非活性状态。我们怀疑TTP的持续失活阻止了炎症的消退，就像一个有故障的刹车。我们相信，通过恢复TTP的功能，有效地修复受损的刹车，将有可能减少炎症。为此，我们计划使用两种不同的药物，我们预测这两种药物将TTP从非活动状态转换为活动状态。其中一种药物已经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。如果这项工作取得成功，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，这种方法是基于促进解决而不是阻断炎症触发因素。