Research Questions
-
What are the ubiquitin-mediated signalling events that limit the damage caused by misfolded protein accumulation under acute stress in healthy cells?
-
How does proteostasis network dysregulation contribute to establishment and maintenance of senescent cellular states?
We use a multi-disciplinary experimental approach, with an emphasis on employing the appropriate tool(s) for the job, and developing new tools whenever required. Our current focus includes:
- multi-dimensional proteomics to quantify misfolded protein ubiquitylation and aggregation in diverse biological samples.
- live-cell imaging sensors to measure dynamics of biomolecular condensates with single-molecular resolution.
- 3D in vitro models (e.g., organoids) to model cellular senescence under more physiological settings.
Current Research
Understanding the interplay between loss of proteostasis and cellular senescence
Loss of proteostasis and cellular senescence are two well-established hallmarks of “normal” ageing, and are linked to almost all major ageing-associated chronic diseases. We are systematically investigating the inter-dependence of these two ageing hallmarks, with the goal of identifying proteostasis network vulnerabilities that could be exploited therapeutically to modulate the senescent cellular state.
Decoding ubiquitin chain signals in physiologic and stressed states
Although Lys48-linked ubiquitin is the canonical signal for protein clearance by the proteasome, ‘alternative’ ubiquitin signals play critical yet poorly-characterised roles in misfolded protein clearance—especially under acute stress. Using linkage-specific ubiquitin probes and perturbation tools, we are uncovering how these additional ubiquitin signalling events maintain proteome robustness in a range of physiologic and stressed cellular contexts.