Lysosome Dysfunction

Lysosomes are multifunctional signalling hubs within mammalian cells as well as the terminal degradative compartments of the cell's autophagic and endocytic pathways. Over half of all commercially available drugs contain at least one basic amine and are potentially lysosomotropic. The drawbacks of lysosomotropic compounds, which may cause lysosome dysfunction, represent a significant hurdle in drug development. The research project will: (i) Use cell imaging combined with gene knockdown/knockout approaches to study the molecular machinery of the lysosome fusion and regeneration cycle and of lysosome/endolysosome signalling in healthy cells and under conditions of lysosome dysfunction; (ii) Develop reagents and cell systems to study the cell biology and function of lysosomal phospholipase A2, an enzyme implicated in drug-induced phospholipidosis; (iii) Identify and characterize new probes, substrates and assays to evaluate lysosome dysfunction in mammalian cells.