Understanding the crosstalk between cell survival and death pathways
In addition to a role in regulating apoptosis, the BCL-2 pro-survival proteins have also been described as key regulators of autophagy. Autophagy is a catabolic degradation process induced in response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolism. As such, it is primarily a cell survival mechanism. Given the opposing functions of autophagy and apoptosis, it is conceivable that bidirectional regulation of both processes dicates whether a cell lives or dies. We are interested in identifying the molecular factors that enable this crosstalk.
The aims of this research are two-fold. Firstly, the role of BCL-2 pro-survival proteins in regulating autophagy is highly contentious with a dearth of in vivodata supporting a role for BCL-2 proteins in regulating autophagy in normal physiology. Using early biochemical and cell-based data, we have now engineered unique mouse models in which interactions between BCL-2 pro-survival proteins and a key inducer of autophagy have been enhanced or diminised. These mice provide an innovative approach to obtaining direct in vivo evidence for this contentious issue.
Secondly, we aim to use modern experimental approaches such as CRISPR/Cas9 gene editing and proteomics/mass spectrometry to screen for novel factors that regulate the crosstalk between autophagy and apoptosis. Success in the identification of physiologically relevant mediators of cell survival and death is fundamental to our understanding of normal physiology and for understanding how these processes can give rise to cancer when things go awry.