If the environment become alkaline, some pathogenic fungi undergo a change in shape that is a prelude to becoming virulent, but even in budding yeast – perhaps the most studied eukaryotic cell – we do not understand how cells survive the stress caused by alkalinity.
In this project, you will use a combination of microfluidics, time-lapse microscopy, molecular biology, and simple mathematical modelling to determine the strategy used by budding yeast to survive alkaline stress. We have developed technology that allows us to follow hundreds of single cells over time in environments that we are able to change in seconds. With a special fluorescent protein that reports intracellular pH, you will use this technology to expose cells to both rapid and gradual changes in alkalinity and phenotype cells both by their ability to maintain their intracellular pH and by their fitness through simultaneously measuring single-cell growth rates.
Cells modify intracellular concentrations of ions in this stress, particularly calcium, sodium, and phosphate, using signalling networks that are conserved in pathogens, such as the calcineurin pathway. By measuring levels of ion channels through tagging with fluorescent proteins and by determining the fitness of mutants with particular channels deleted, you will discover why budding yeast modifies ionic concentrations in this way and confirm your understanding by integrating the results into a mathematical model.
Finally, you will extend your results to the pathogen Candida glabrata by predicting and testing which deletions of ion channels make this yeast particularly vulnerable to alkaline stress.
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