My laboratory is interested in the molecular mechanisms underlying the activation and development of the immune system. In addition to studying select MAPK pathways, we have focused on the activation pathways and functions of the NF-kB transcription factor complexes. We were among the first laboratories to clone NF-kB genes. NF-kB is critical to innate and adaptive immune activation. It transcriptionally induces many immunoregulatory proteins, such as cytokines and chemokines in response to invasion by pathogens. NF-kB is also critical to the propagation of various viruses, including the human immunodeficiency virus (HIV). Finally, NF-kB factors are essential for the survival of numerous cells, especially developing cells, because they induce expression of anti-apoptotic proteins. Given these functions of NF-kB in health, inappropriate or unwanted activation in disease drives inflammatory reactions, autoimmunity and transplant rejection. NF-kB is also frequently inappropriately activated in tumor cells, assuring survival and driving tumorigenesis.

The roles of NF-kB in disease make it and its regulators attractive targets for therapeutic intervention. It is thus critical to fully understand the many functions and pathways of regulation of NF-kB in order to identify novel and optimal targets to very selectively interfere with NF-kB in specific disease contexts.

In my laboratory we investigate mechanisms of activation of NF-kB initiated by antigen receptors (B and T cell receptors), Toll receptors and members of the TNF receptor family, as well as other signals. In the past we have made significant contributions to our present understanding of how classical activation of NF-kB proceeds via regulated and rapid degradation of IkB inhibitory proteins. The present research includes identification of novel receptor-pathway specific signaling molecules and their mechanisms of action; it also includes generation and analysis of mice deficient in such signaling molecules to identify the relevant biologic contexts. We have discovered a novel, non-classical activation path important for the development of B cells, osteoclasts and mammary glands. This pathway appears to be active in several autoimmune conditions. Finally our research into activation pathways is focused on identifying mechanisms by which various tumor cells constitutively activate NF-kB.

We investigate the functional roles of NF-kB through generation and analysis of mice deficient in various components of the NF-kB family of polypeptides. In the past we have uncovered previously unknown roles of NF-kB in the development of B cells and osteoclasts. Mice lacking the appropriate components exhibit severe osteopetrosis and lack mature B cells. We have also discovered unique roles of NF-kB factors in combating pathogens, such as Toxoplasma gondii. We continue to identify defects in various knockout mice and to elucidate the underlying molecular mechanisms. In addition, we determine the specific critical targets of NF-kB in both health and disease contexts by gene profiling studies. These efforts have and will continue to reveal novel targets for therapeutic intervention in many diseases.

Selected Publications: