A structure-function analysis of USP7 and NF-kB interaction.

炎症是人体免疫系统对有害刺激的复杂生物反应，如微生物、组织损伤或刺激物。这是一种保护性的尝试，目的是消除损伤的原因，并启动受影响组织或器官的愈合过程。在没有炎症的情况下，伤口和感染永远不会愈合，受影响组织的逐渐破坏最终会导致严重疾病或死亡。然而，不加控制的炎症也会导致一系列疾病，包括炎症性肠病、类风湿性关节炎、自身免疫、败血症和动脉粥样硬化。最近的研究也揭示了未调节或失调的炎症过程在癌症和神经变性中的作用。这项拟议的研究将集中在一系列统称为核因子kappaB(NF-kB)的蛋白质上。核因子-kB是基因表达的关键调节因子，在感染和炎症的免疫反应中发挥关键作用。这种反应的触发因素可能包括微生物或其相关产物以及来自邻近细胞或组织的信号。这些刺激诱导核因子-kB增加前炎症因子，如细胞因子和趋化因子的编码基因的表达，这些因子协调免疫细胞向感染或损伤部位的移动和激活。虽然这些过程对于清除感染和修复受损组织是必不可少的，但它们对健康组织构成严重威胁，并可能在炎症区域造成严重损害。因此，核因子-kB对这些促炎介质的表达通常受到严格控制。然而，在某些疾病中，包括上面列出的那些，核因子-kB没有得到充分的调控，这些潜在的有害炎症介质的持续表达发生了。因此，在炎症性疾病的治疗中，核因子-kB被认为是开发预防炎症的新疗法的重要靶点。近年来，有研究表明，控制破坏核因子-kB蛋白是免疫系统减少促炎因子产生的重要途径。我们之前的研究发现了一种名为USP7的蛋白质，它通过直接与核因子-kB相互作用来防止它的破坏。我们假设，干扰这两种蛋白的相互作用将降低核因子-kB蛋白水平，从而减轻炎症。在这项建议中，我们的目标是详细了解USP7和核因子-kB是如何相互作用的，并研究干扰这种相互作用对免疫细胞功能的影响。这些研究提供的信息可能被用来在未来开发抑制核因子-kB活性的新药，以减少炎症性疾病治疗中的炎症。

Inflammation is the complex biological response of the body's immune system to harmful stimuli, such as microbes, tissue damage or irritants. It is a protective attempt to remove the cause of injury as well as initiate the healing process for the affected tissue or organ. In the absence of inflammation, wounds and infections would never heal and progressive destruction of the affected tissue would eventually lead to serious illness or death. However, inflammation which runs unchecked can also lead to a host of diseases including inflammatory bowel disease, rheumatoid arthritis, autoimmunity, sepsis and atherosclerosis. Recent research has also revealed a role for unregulated or dysregulated inflammatory processes in cancer and neurodegeneration. The proposed research will focus on a family of proteins collectively known as Nuclear Factor kappaB (NF-kB). NF-kB is a critical regulator of gene expression and plays key roles in the immune response to infection and inflammation. The triggers of such responses may include microbes or their associated products as well as signals from neighbouring cells or tissues. These stimuli induce NF-kB to increase the expression of genes that encode for pro-inflammatory factors such as cytokines and chemokines which orchestrate the movement and activation of immune cells to sites of infection or injury. While these processes are essential for the clearance of infection and the repair of damaged tissue, they pose serious threats to healthy tissue and can cause severe damage in areas of inflammation. For this reason the expression of these pro-inflammatory mediators by NF-kB is normally tightly controlled. However in certain diseases, including those listed above, NF-kB is inadequately regulated and sustained expression of these potentially harmful mediators of inflammation occurs. As a result, NF-kB is considered an important target for the development of new therapies to prevent inflammation in the treatment of inflammatory diseases.In recent years it has emerged that the controlled destruction of NF-kB proteins is an important way used by the immune system to reduce the production of pro-inflammatory factors. Our previous studies discovered a protein called USP7 that prevents the destruction of NF-kB by interacting directly with it. We hypothesise that interfering with the interaction of these two proteins will reduce NF-kB protein levels and thereby reduce inflammation. In this proposal we aim to understand in detail how USP7 and NF-kB interact and to investigate the consequences of interfering with this interaction on the function of immune cells. The information provided from these studies could be used to develop new drugs in the future that inhibit NF-kB activity to reduce inflammation in the treatment of inflammatory disease.