Project
Investigating mechanisms of cobalt induced neurotoxicity with reference to metal ion release in patients with metal-on-metal hip replacements
Supervisor(s)
Dr Susan Currie, Dr Susan Chalmers,
Area
Target Validation, Neuroscience, Cellular Signalling
Description
Wear debris from cobalt-chromium metal-on-metal (MoM) hip prostheses release cobalt and chromium ions into patients' circulation. The cobalt ions disseminate throughout the body, and at high concentrations are associated with adverse effects such as neurotoxicity. Cobalt is a mobile ion and enters most organs, including the brain and heart. When exposed to high circulating cobalt concentrations, MoM patients display multiple systemic adverse effects including neurological symptoms such as auditory and visual impairment, peripheral neuropathy and cognitive decline, in addition to cardiomyopathy and hypothyroidism. The orthopaedic community has only recently become aware of the correlation between the presence of a MoM implant, high circulating cobalt levels, and neurological and cardiac symptoms, and there is little information on the mechanism(s) responsible. It has recently been found that patients with MoM implants in situ show subtle brain dysfunction with decreased brain activity. Dysregulation of glutamate/calcium signalling, and altered phosphorylation of calcium/calmodulin-stimulated protein kinase II (CaMKII) may play a causal role in neurotoxicity. Cobalt is also known to disrupt mitochondrial function and it has been shown that CoCl2 activates mitochondrial dependent cell death in neuroblastoma cells in vitro, causing collapse of the essential mitochondrial transmembrane potential, which may also contribute to neurotoxicity.
This project will measure the effects of cobalt on the electrical activity and mitochondrial functions of neuronal tissue and cells isolated from the hippocampus of neonatal rats to investigate the mechanisms responsible for cobalt-induced toxicity. It is our novel hypothesis that cobalt toxicity alters the activity of CaMKII, a regulator of calcium homeostasis in cells. Dysregulation of CaMKII is linked to neurological disorders including Alzheimer's disease. The opportunity to stabilise and archive tissues from this study with RNAlater will allow for future work where we can identify biomarkers associated with cobalt toxicity with a view towards developing new diagnostic and therapeutic approaches. The project involves inter-departmental collaboration between SIPBS and Biomedical Engineering and combines expertise across neuroscience and mitochondrial function (Dr Chalmers), CaMKII (Dr Susan Currie), Molecular Biology (Dr Roth Tate) and cobalt toxicity (Prof Helen Grant).Techniques
Neuronal cell isolation and culture, cell imaging and immunofluorescence, immunoblotting, immunoprecipitation, mitochondrial functional assays, siRNA work
References
Afolaranmi G.A. et al, J Biomed Mater Res, 100, 1529-38, 2012
Ashpole N.M. et al, J Biol Chem 287, 8495-8506, 2012
Clark M. et al, Spotlight No 0079, Annual Orthopaedic Research Society meeting, Spring 2012
Green D.R. et al, Science 345, 1250256, 2014
Gunning et al, J Neural Eng 10, 016007, 2013
Laovitthayanggoon S. et al, Heart J. 103, A4, 2017
Litke et al, IEEE Trans. Nuclear Science, 51, 1434-1440, 2004
Mao X. et al, Medical Journal of Australia 194, 649-51, 2011
Skelding K.A. et al, J Cerebral Blood Flow & Metabolism 32, 2181-91, 2012
Stenger C. et al, Int. J. Oncology 39, 601-9, 2011
Tower S.S. et al, J Bone & Joint Surgery 92, 2847-51, 2010