Dissecting the function of Bcl-3 in NF-kB signaling in B cells.

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In healthy people, the immune system can recognise, attack and destroy potentially harmful infectious agents wherever they are in the body, while avoiding mounting similar attacks against healthy cells and tissues. However, aberrant or inappropriate immune responses can lead to chronic or overwhelming infection, or contribute to the development of a host of autoimmune or chronic inflammatory diseases, such as Crohn's disease, rheumatoid arthritis, and atherosclerosis. In fact, it is now clear that inflammation and the immune system contribute to virtually all diseases in humans, including cancer and neurodegeneration. Moreover, the accumulation of DNA mutations in cells of the immune system leads to the development of lymphomas and leukaemias. 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 biological and pathological processes driven by the immune system are profoundly influenced by how immune cells detect and respond to their environment. 'Molecular signals' received at the surface of immune cells are conveyed to the cell's nucleus where they are integrated and interpreted, leading to alterations in the profile of genes 'expressed' by that cell. This in turn leads to fundamental changes in the molecular constituents of the entire cell, which ultimately determines its biological or pathological function. Arguably the most important molecules regulating immune cell responses in this way are a family of intracellular proteins collectively known as Nuclear Factor kappaB (NF-kB). These proteins are critical for changing gene expression in immune cells in response to a wide variety of molecular signals emanating from either neighbouring cells or from invading pathogenic microorganisms. As a result, they are of fundamental importance in the development, maintenance and function of the immune cells, and contribute to both beneficial and detrimental immune responses. 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. The current application aims to determine the function of Bcl-3, a protein present in the nucleus of immune cells that is known to influence NF-kB function. Bcl-3 is found in many different types of cells, but it plays particularly prominent roles in the biology of B cells. These are important immune cells because they have the capacity to make antibodies, and antibodies contribute to all beneficial and detrimental immune responses. Bcl-3 controls the survival, proliferation and immune function of B cells, while too much Bcl-3 can lead to the development of B cell-derived lymphomas and leukaemias. However, it is far from clear how Bcl-3 does these things. The work we are proposing exploits and integrates state-of-the-art technologies to examine the importance of Bcl-3 at the molecular, cellular and whole animal level. The results of our study will provide novel and unprecedented insights into how normal and elevated levels of this protein regulate B cell biology, and these findings will have broad physiological and pathological implications. In addition, and importantly, they will provide a firm foundation upon which we can further explore the therapeutic potential of blocking or mimicking Bcl-3 function.