When apoptotic cell death goes wrong, the results are often cancer or autoimmune diseases. My laboratory aims to illuminate critical "black boxes" in the apoptotic pathway.
We are focusing on how the killer Bak and Bax proteins irreversibly commit cells to die, and how these proteins are regulated. Understanding this process is critical to developing new treatments that either enhance or block apoptosis in diseased cells.
Our research program uses biochemical, cell biological and structural approaches to examine Bak and Bax function, and thus identify potential means of specifically regulating apoptotic cell death in cancer and other diseases.
We have found that following major conformation changes, both Bak and Bax form symmetric homodimers that act as the basic unit of the apoptosis pore. We are now using different strategies to determine how dimers interact to form the large complexes thought necessary to form a pore in the mitochondrial outer membrane.
We have also recently discovered that a new site in Bak can be targeted by antibodies to trigger conformation change and pore formation. Antibodies to the same site in Bax can block apoptosis. Ongoing studies are addressing whether this new site can be targeted by intrabodies or small molecules to directly regulate Bak and Bax.