Main Field(s) of Research, Abstract
Cell Death and Regulation of Inflammation
Cell death is a necessary biological event – however, excessive or inhibition of cell death often aids in the development of a disease by increasing cell survival or causing inflammation in the microenvironment. Unsurprisingly, there are several pathways leading to cell death: apoptosis, which includes both intrinsic (mitochondria) and extrinsic (death receptor) pathways and more recently programmed necrosis or necroptosis.
We are interested in studying proteins that regulate cell death, specifically inhibitors of apoptosis proteins (IAPs) and receptor interacting Serine/Threonine protein kinase (RIPK). Both these protein families are vital for signaling downstream of tumor necrosis factor (TNF) superfamily signaling and RIPK3 in particular has been shown to regulate programmed necrosis. We and others have shown these proteins directly regulate key cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF) (Vince et al., Immunity 2012, Wong et al., Blood 2014). This suggests that the proteins involved in regulating cell death also are critical to regulating signaling networks controlling production of cytokines/chemokines making the proteins good targets for small molecule inhibition. Indeed, Smac mimetics (IAP inhibitors) are now in Phase II clinical cancer trials and compounds directed against RIPK1 and RIPK3 have been developed.
We are interested in understanding these signaling networks, the cytokines/chemokines regulated directly by these proteins and what disease settings may benefit from inhibition of these proteins, such as in ‘ovarian’ cancer and metastasis. To achieve our goals, we utilize animal models, conditional gene knockouts, biochemical and molecular techniques using established cell lines from our knockouts for structure:function analysis.
Masters positions are available.