Research in our laboratory is focused on understanding how engagement of receptors of both the innate and adaptive immune system lead to the activation of appropriate cellular responses through the inducible transcription factor, NF-kB. NF-kB plays a critical role in regulating the expression of a large number of genes involved in immune, inflammatory and apoptotic processes. NF-kB can be activated by different stimuli such as microbial products, proinflammatory cytokines, T and B cell mitogens and physical and chemical stresses. NF-kB in turn regulates the inducible expression of many cytokines, chemokines, adhesion molecules, acute phase proteins and anti-microbial peptides. Therefore NF-kB plays a central, evolutionarily conserved role in coordinating immune and inflammatory responses. In unstimulated cells, NF-kB is retained in the cytoplasm through its interaction with the inhibitory IkB proteins. Stimulation of cells with different inducers leads to the phosphorylation and subsequent degradation of the IkB proteins. Upon degradation of IkB, the free NF-kB enters the nucleus, however translocation of NF-kB to the nucleus is, in itself, not sufficient to drive transcription of target genes. Instead, specific phosphorylation of one of the NF-kB subunits, p65/RelA, is required for both efficient DNA-binding and transcriptional activity of the nuclear NF-kB.
We wish to understand the mechanisms that operate in the signal transduction pathways that lead to NF-kB activation, as well as the regulatory mechanisms that control the activity of NF-kB in the nucleus. Specific projects that are underway at present are listed below.
1. Understanding the mechanism by which signals from Toll/IL-1 receptors, TNF receptor and the T-cell receptor lead to NF-kB activation.
2. Characterizing the mechanism by which the transcriptional activity of nuclear NF-kB is regulated.
3. Exploring the dysregulation of NF-kB activity in diseases such as arthritis and cancer.
4. Understanding the biology of novel Toll-like receptors in response to infection.