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Investigating NF-kappaB p50 phosphorylation and the regulation of transcription

研究 NF-kappaB p50 磷酸化和转录调控

基本信息

批准号：
MR/M010694/1
负责人：
Ruaidhri CARMODY
金额：
$ 80.73万
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：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FM010694%2F1
关键词：
Investigating NF kappaB p50 phosphorylation

项目摘要

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 injurious stimuli as well as initiate the healing process for the affected tissue. 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. It is for this reason that inflammation is normally tightly regulated by the body. Thus, a thorough knowledge of the immune system and immune cells is of fundamental biological importance, and has the potential to improve our understanding and treatment of a broad spectrum of human diseases.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.We are broadly interested in understanding how these complex intracellular processes are orchestrated and regulated, with a view to developing new therapies that manipulate immune cell function to control disease. In recent years it has emerged that the modification of individual NF-kB proteins by the addition of phosphate groups, a process termed phosphorylation, plays a critical role in determining the pattern of genes activated during inflammation. In this proposal we aim to comprehensively investigate the phosphorylation of NF-kB and how this modification contributes to the regulation of inflammation. The work we are proposing exploits and integrates state-of-the-art technologies to examine the importance of NF-kB phosphorylation at the molecular, cellular and genomic level. We will also incorporate computational modelling of the complex intracellular processes regulating NF-kB phosphorylation to predict potential therapeutic targets in inflammatory disease. The results of our study will provide novel and unprecedented insights into how the control of NF-kB phosphorylation contributes to the regulation of inflammation with broad physiological and pathological implications. The data generated will be relevant to our understanding of human diseases where NF-kB has been demonstrated to be important, such as inflammatory disease and cancer, and will be important in directing future therapeutic strategies aimed at inhibiting inflammation.

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，可以去除有害的刺激，并启动受影响组织的愈合过程。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。正是由于这个原因，炎症通常是由身体严格调节的。因此，对免疫系统和免疫细胞的全面了解具有基本的生物学重要性，并有可能提高我们对广泛的人类疾病的理解和治疗。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，并可能在炎症区域造成严重损伤。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。我们对了解这些复杂的细胞内过程是如何协调和调节的广泛感兴趣，以期开发新的疗法，操纵免疫细胞功能来控制疾病。近年来发现，通过添加磷酸基团对NF-kB蛋白进行修饰，这一过程被称为磷酸化，在确定炎症期间激活的基因模式方面起着关键作用。在本提案中，我们旨在全面研究NF-kB的磷酸化以及这种修饰如何有助于炎症的调节。我们提出的工作利用并整合了最先进的技术，以检查NF-kB磷酸化在分子，细胞和基因组水平上的重要性。我们还将纳入调节NF-kB磷酸化的复杂细胞内过程的计算模型，以预测炎症性疾病的潜在治疗靶点。我们的研究结果将为NF-kB磷酸化的控制如何促进炎症的调节提供新颖和前所未有的见解，具有广泛的生理和病理意义。所产生的数据将与我们对NF-kB已被证明重要的人类疾病的理解相关，例如炎症性疾病和癌症，并将在指导未来旨在抑制炎症的治疗策略方面发挥重要作用。