Investigating NF-kappaB p50 phosphorylation and the regulation of transcription

点击翻译按钮获取中文摘要

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.