DISSECTING THE FUNCTION OF INDIVIDUAL NF-kappaB SUBUNITS IN INFLAMMATION

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.

NF-kappaB plays a pivotal role in immunity and inflammation and is considered to be a prime candidate for drug development. The fundamental goal of this proposal is to identify NF-kappaB subunit specific regulatory events in a human immune response. I propose to systematically determine the genes whose expression is dependent on specific NF-kappaB dimeric complexes in primary human dendritic cells exposed to bacterial products and to characterise the functional genetic elements which select these complexes. The project builds on my existing expertise and available genomic and computational approaches and develops new ways for studying transcriptional gene regulation, such as the genetic manipulation of human cells, previously achievable only in animal models. It will generate new reagents for quantitative analysis of cellular responses available to the scientific community. The identification of NF-kappaB subunit specific regulatory events will provide an alternative path for the development of targeted therapeutic strategies for treating immune disorders.