Grant: Project Grant

Clear relationships exist between lysosome activity, cancers and age-related diseases but many fundamental aspects of lysosome biology remain enigmatic preventing development of effective therapies: Lysosomes are membrane-encapsulated organelles responsible for recycling biomaterials within all eukaryotic cells, like the trillions that make up you and I. As important sources of nutrients, growing and dividing cells rely on lysosomes especially when starved, as is the case for cancer cells in tumor environments. But lysosomes generate molecules called reactive oxygen species that damage their membranes, causing them to rupture and kill cells. However, for reasons unknown, lysosome membranes within cancer cells are resistant to rupture. Aging brain cells also depend on lysosomes to clear toxic protein aggregates. Loss of this function leads to premature cell death underlying many age-related diseases, like Alzheimer's disease. Often this correlates with abnormal accumulation of lipids called diacylglycerol, ceramide and sphingosine on lysosome membranes that promote dysfunction and rupture. But it is unclear how lysosomes handle these lipids to function and remain intact. Furthermore, enhanced lysosome activity in both cases relies on inhibition of TOR signaling, an important mediator of cell metabolism - but the molecular basis of how this occurs is not entirely understood. The aim of this project is to better understand the basis of these three aspects of lysosome biology relevant to cancer and age-related diseases by studying baker's yeast as a model organism. I suspect that a process that my lab discovered called the IntraLumenal Fragment (ILF) pathway is responsible and will test this hypothesis using microscopy, genetic and biochemical techniques. Knowing the basis of lysosome activation and rupture will facilitate the development new therapies for these devastating diseases that affect millions of Canadians.