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

USP7 和 NF-kB 相互作用的结构功能分析。

• 批准号: BB/T007427/1
• 负责人: Ruaidhri CARMODY
• 金额: $ 73.73万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT007427%2F1
• 关键词: structure; function; analysis; USP7; NF

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.

炎症是人体免疫系统对有害刺激（如微生物、组织损伤或刺激物）的复杂生物反应。这是一种保护性的尝试，旨在消除受伤的原因，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的疾病或死亡。然而，不受控制的炎症也会导致一系列疾病，包括炎症性肠病、类风湿关节炎、自身免疫、败血症和动脉粥样硬化。最近的研究也揭示了不受调节或失调的炎症过程在癌症和神经变性中的作用。拟议的研究将集中在一个被统称为核因子κ b （NF-kB）的蛋白质家族上。NF-kB是基因表达的关键调控因子，在感染和炎症的免疫反应中起关键作用。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NF-kB增加编码促炎因子的基因的表达，如细胞因子和趋化因子，它们协调免疫细胞向感染或损伤部位的运动和激活。虽然这些过程对于清除感染和修复受损组织至关重要，但它们对健康组织构成严重威胁，并可能导致炎症区域严重损伤。因此，NF-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，包括上面列出的疾病，NF-kB被不充分调节，这些潜在有害的炎症介质的持续表达发生。因此，NF-kB被认为是开发炎症性疾病治疗中预防炎症的新疗法的重要靶点。近年来，人们发现有控制地破坏NF-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叫做USP7的蛋白质，它通过直接与NF-kB相互作用来阻止NF-kB的破坏。我们假设干扰这两种蛋白的相互作用会降低NF-kB蛋白水平，从而减少炎症。在本提案中，我们的目标是详细了解USP7和NF-kB如何相互作用，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用于未来开发抑制NF-kB活性的新药，以减少炎症性疾病治疗中的炎症。