DISSECTING THE FUNCTION OF INDIVIDUAL NF-kappaB SUBUNITS IN INFLAMMATION

炎症是对感染和损伤的正常生理反应，但如果过度引发，可能会导致广泛的组织损伤和残疾。持续性炎症反应的病理后果包括各种自身免疫性疾病，如类风湿性关节炎、克罗恩？S病、强直性脊柱炎和多发性硬化症。持续的炎症反应通常与炎症分子产生的调控中断有关。在正常的自我解决的身体对感染或损伤的反应中，炎症分子会在一段确定的时间内产生，而在慢性自身免疫条件下，它们的产生会延长。许多炎性分子的产生受一种称为核因子-kappaB的关键调控蛋白家族的控制。所有五种核因子-kappaB蛋白都存在于炎症部位，并具有活性，但时间不同。为什么有五种相似但不完全相同的核因子-kappaB蛋白，为什么它们在不同的时间到达和离开炎症部位，以及它们如何控制炎症分子的产生水平和长度，这是本研究的主题。了解每一种核因子-kappaB蛋白的功能及其调节的分子对于开发新一代治疗方法非常重要。这些只针对特定的细胞事件，而不会干扰全球宿主防御机制。这也将帮助科学家更好地理解为什么我们有这么多表面上相似的蛋白质家族，以及它们拥有哪些特定的功能。这项研究将由帝国理工学院肯尼迪风湿病研究所的伊琳娜·乌达洛娃博士进行，并将以实验室为基础，使用新的基因组技术和计算方法。拟议的新技术将取代在研究中使用动物。这项研究产生的成果将通过同行评议的科学期刊和肯尼迪研究所的年度报告传达，并在科学会议上提出。

Inflammation is a normal physiological response to infection and injury, but can lead to extensive tissue damage and disability when elicited in excess. Pathological consequences of sustained inflammatory response include variety of autoimmune diseases, such as rheumatoid arthritis, Crohn?s disease, ankylosing spondylitis and multiple sclerosis. A sustained inflammatory response is often linked to the break down in regulation of production of inflammatory molecules. In a normal self-resolving body response to infection or injury inflammatory molecules are produced for a defined period of time, while in chronic autoimmune conditions their production is prolonged. The production of many inflammatory molecules is controlled by a key family of regulatory proteins called NF-kappaB. All five NF-kappaB proteins are present at the site of inflammation and are active, but at different times. Why there are five similar but not identical NF-kappaB proteins, why they come to and leave the site of inflammation at different times and how they control the level and the length of production of inflammatory molecules is a subject of this investigation. Understanding how each NF-kappaB protein functions and what molecules it regulates is important for the development of a new generation of therapeutic approaches. These would only target specific cellular events without interfering with the global host defence mechanisms. It will also help scientists to better understand why we have so many families of ostensibly similar proteins and what specific functions they hold.The research will be carried out by Dr Irina Udalova at the Kennedy Institute of Rheumatology, Imperial College, and will be laboratory based using novel genomic techniques and computational methods. The proposed novel techniques will replace the use of animals in research. Results generated in this study will be communicated through peer-reviewed scientific journals and through annual reports from the Kennedy Institute and presented at scientific meetings.