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Mitochondrial calcium in neurodegeneration (PhD in Biological Science at the MRC Mitochondrial Biology Unit)

  • Full or part time
  • Application Deadline
    Tuesday, June 30, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Mitochondrial calcium plays a key role in a wide array of cellular homeostatic processes as diverse as bioenergetics and cell death, and has been linked to disease conditions as varied as cancer, ischemia-reperfusion injury and neurodegeneration (1-3). The research in our lab is focussed on understanding the causes of various neurodegenerative diseases, such as Parkinson’s and Motor Neuron Disease, with a particular interest in mechanisms relating to mitochondrial dysfunction, and to identify potential therapeutic interventions. To do this we take a multi-disciplinary approach to combine molecular cell biological techniques with the powerful genetic model, Drosophila melanogaster.

We have developed a comprehensive genetic toolkit to manipulate mitochondrial calcium uptake via the Mitochondrial Calcium Uniporter complex (4). Recently, using these models we have found that reducing mitochondrial calcium uptake is beneficial in a range of neurodegenerative disease models. This project will be to further characterise this interaction as a potential therapeutic avenue, and to understand the molecular basis behind the sensitivity of these disease conditions to mitochondrial calcium.

The experimental aims will encompass a wide range of techniques including Drosophila genetics, likely including CRISPR/Cas9-mediated genomic engineering, live-imaging techniques to analyse mitochondrial calcium dynamics, as well as behavioural and neuro-functional assays. Molecular techniques will also be employed to analyse changes to the metabolome and metabolic pathways that may underpin the consequences of dysregulated mitochondrial calcium handling. Insight into these pathogenic and homeostatic mechanisms will give us a greater understanding of the causes of these diseases and illuminate potential therapeutic avenues.

Competitive applicants will have or expect to achieve a high degree classification from a leading university, with excellent knowledge and experience within the fields of cell biology, genetics and the use of small model organisms in modelling human disease. They will also be expected to have substantial lab experience in molecular, cell biology and/or genetic techniques.


Keywords: Neuroscience, Cell Biology, Genetics, Neurodegeneration, Mitochondria, calcium, Parkinson’s disease, Motor Neuron Disease, Drosophila.


Funding Notes

(Full funding available for UK and EU applicants; others can apply if they wish)

References

1. Granatiero V, De Stefani D, Rizzuto R. Mitochondrial Calcium Handling in Physiology and Disease. Adv Exp Med Biol. 2017;982:25-47.

2. Mammucari C, Raffaello A, Vecellio Reane D, Rizzuto R. Molecular structure and pathophysiological roles of the Mitochondrial Calcium Uniporter. Biochim Biophys Acta. 2016;1863(10):2457-64.

3. Liao Y, Dong Y, Cheng J. The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders. Int J Mol Sci. 2017;18(2).

4. Tufi R, Gleeson TP, von Stockum S, Hewitt VL, Lee JJ, Terriente-Felix A, Sanchez-Martinez A, Ziviani E, Whitworth AJ. Comprehensive Genetic Characterization of Mitochondrial Ca(2+) Uniporter Components Reveals Their Different Physiological Requirements In Vivo. Cell Rep. 2019;27(5):1541-50 e5.

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