Regulation of inflammatory signalling by ubiquitination

Proper regulation of inflammatory responses is important to avoid development of diseases such as chronic inflammation and cancer. To be able to control unwanted inflammation, flexible but precise mechanisms are required to tune inflammatory signals in the cells. To find molecular switches that may be used to target inflammatory signalling, we aim at understanding how inflammation is regulated in cells at the molecular level.

A major regulator of inflammation is the NF-κB family of transcription factors, and these factors are chronically active in many inflammatory diseases. Post-translational modifications such as ubiquitination increase the possibilities to regulate protein functions, and my laboratory studies how signalling mediated via ubiquitination regulates the NF-κB signalling pathways. As regulation of inflammation is very complicated in mammalian cells, we use the fruit fly Drosophila melanogaster as a model organism. The signalling mechanisms controlling as well ubiquitination as NF-κB responses are well conserved between mammals and flies, hence, Drosophila serves as an excellent model organism to study the basic principles of this inflammation-promoting signalling pathway.

As ubiquitination is a post-translational modification that is induced and removed in a regulated, flexible manner, it may be used as a drug target for tuning inflammatory signalling. To be able to target ubiquitination, we will investigate how ubiquitination patterns are changed during inflammation. Further, we aim to find regulators of ubiquitination as well as to determine executors of ubiquitin signalling in the NF-κB pathways. Pinpointing the changes in ubiquitination during inflammation may also allow us to develop new diagnostic markers for inflammation. As intestinal inflammation is a specific interest of ours, and as the Drosophila intestine is a recognised and convenient model for intestinal disease, we are particularly interested in targeting ubiquitination events in intestinal inflammation. As an approach to target molecules to specific cell populations of the intestinal epithelium, we will use nanoparticle-mediated delivery, an elegant and precise method that also is suitable for development of diagnostic markers for inflammation.