Investigating the impact of metallic nanoparticles on biological systems and lysosomal function.

There is increasing use of metallic nanoparticles (MNP) in biomedicine (bioimaging, nanotherapeutics and cellular/organelle purification), also in numerous everyday products, due to their large number of chemical applications and range of important properties (silver nanoparticles in fabric to kill bacteria and for odour-resistance) and potentially in environmental settings (iron nanoparticles to clean pollution in ground water). However, despite our increasing exposure to MNPs their toxicity in biological systems remains largely undefined, despite obvious implications in human health, ecosystem safety and for safety of the many new potential positive uses of this developing technology.
It has been shown that MNPs can somehow enter the brain and may be detrimental to health. This is of particular concern as it has been shown that they can be produced during dental surgery giving an obvious route into the human body.
Unsurprisingly, MNPs that enter human cells accumulate in the lysosomes and can enhance lysosomal function. For example, it has been shown that MNPs produced by dental sonochemistry aid the clearance of bacteria and that acidifying MNPs enhance lysosomal function and clearance of protein aggregates in Alzheimer's. However, they may also have disrupting functions, as demonstrated by a study that found that the acidic lumen of the lysosome damages some nanoparticles, leading to free heavy metal accumulation and dysfunction associated with neurodegenerative diseases and compromised immune function. This project could therefore have implications in other important neurodegenerative diseases such as Huntingdon's.
This project encompasses a multidisciplinary programme of research at the interface between chemistry and cell biology, analysing the impact of different MNPs on lysosomal function in health and disease. Specifically, this PhD would cover research on the effects that composition and size of MNPs may have on lysosomal function in vivo and in vitro. Effects would be modelled in cells where MNPs in the body are likely to accumulate (odontoblast, macrophage and microglial cell lines) to determine impacts on lysosomal function and ultimately cell health. This project would also include the use of zebrafish as a whole organism animal model, to determine whether MNP size or composition is a major determinant in their ability to cross the blood brain barrier and induce toxicity. This part of the project would include use of cutting edge lightsheet microscopy, to determine fluorescently labelled MNP localisation within the organism as well as in vivo lysosomal functional assays.
In this way data could be collected on the potential risks to cellular function associated with NMPs which could have a number of wide-reaching effects including for the continued use of this technology and for how it is used in the future. This project would open up a new area of research and would undoubtable lead to a range of further projects in this field.