Investigating Yap as a Novel Therapeutic Target for Rheumatoid Arthritis

风湿性关节炎（RA）是英国最常见的慢性炎症性疾病，影响约1%的成年人。它主要影响关节，并且可以迅速进展，导致关节损伤和破坏性畸形。在英国，与RA相关的总成本估计高达每年60亿英镑。研究主要集中在了解免疫系统和炎症在RA中的作用以及我们如何抑制这种作用，这导致近年来生物制剂治疗的重要进展。然而，两个主要问题仍未得到解决：（i）高达30%的患者对治疗无效，（ii）即使炎症得到成功治疗，关节损伤仍可能发生，这表明仅抑制炎症不足以阻止疾病进展并完全治疗RA。RA的一个关键特征是滑膜炎症（滑膜炎）。该膜覆盖关节或关节腔的内部。在RA期间，滑膜变厚并形成所谓的“血管翳”，导致软骨和骨的破坏。血管翳被认为是一种肿瘤，由膜中细胞的不受控制的生长引起。我们想了解是什么推动了这一进程，并找到阻止这一进程的方法。我们发现一种叫做雅普的特殊蛋白质在关节炎时的滑膜中含量很高。已知这种蛋白质存在于其他组织和器官中，包括肝脏、肠、皮肤和大脑，以刺激组织/器官生长。因此，我们认为雅普可能导致RA滑膜血管翳过度生长。我们将通过使用一个模型来研究这一点，在这个模型中，我们可以激活滑膜细胞中的雅普，我们将确定这是否会导致膜中的细胞过度生长并形成类似于RA期间发生的血管翳。为此，我们将联合收割机并完善我们实验室现有的模型和技术。我们还想知道是否可以通过阻断雅普的活性来预防或减少RA血管翳。我们将通过灭活滑膜细胞中的雅普基因来研究这一点，这样细胞就不能再制造雅普蛋白。我们将在我们实验室可用的RA模型中进行这一研究，并确定这是否可以预防或减少血管翳形成以及软骨和骨破坏。最后，我们将研究最近发现的阻断雅普活性的药物是否可以用于治疗RA。这些研究将增加我们对RA血管翳形成和导致的软骨和骨破坏的理解，并为RA的治疗确定新的治疗靶点。

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease in the UK, affecting ~1% of adults. It mainly affects the joints and can progress rapidly, causing joint damage and devastating deformities. The total costs associated with RA have been estimated to be up to £6 billion per year in the UK. Research has mostly focussed on understanding the role of the immune system and inflammation in RA and how we can suppress this, which has led to important advances in treatment in recent years with the biologics. However, two major problems remain unresolved: (i) up to 30% of patients fail to respond to treatments, and (ii) joint damage can still occur even when inflammation is successfully treated, suggesting that suppression of inflammation alone is not sufficient to stop disease progression and fully treat RA. A key feature of RA is inflammation of the synovial membrane (synovitis). This membrane covers the inside of the joint or joint cavity. During RA, the synovial membrane becomes thicker and forms a so-called "pannus" that is causing the destruction of cartilage and bone. The pannus is considered like a tumour that results from uncontrolled growth of cells in the membrane. We want to understand what drives this process, and find out ways to stop this. We have discovered that a particular protein, called Yap, is very high in the synovial membrane during arthritis. This protein is known in other tissues and organs, including liver, intestine, skin and brain, to stimulate tissue/organ growth. We therefore think that Yap may drive the synovial pannus overgrowth in RA. We will investigate this by using a model in which we can activate Yap in cells in the synovial membrane, and we will determine whether this causes cells in the membrane to overgrow and form a pannus similar to what happens during RA. To this end, we will combine and refine existing models and techniques available in our laboratory.We also want to know if we can prevent or reduce the RA pannus by blocking the activity of Yap. We will investigate this by inactivating the Yap gene in the cells of the synovial membrane, so that cells can no longer make the Yap protein. We will do this in our model of RA available in our laboratory and determine whether this can prevent or reduce pannus formation and cartilage and bone destruction. Finally, we will investigate if a drug that has recently been discovered to block the activity of Yap could be used to treat RA.These studies will increase our understanding of the formation of the pannus and resulting cartilage and bone destructions in RA, and identify a new therapeutic target for the treatment of RA.