MRC DiMeN Doctoral Training Partnership: Cell painting: Illuminating the whole cell to develop treatments for mitochondrial disease

Mitochondrial diseases are the most common inherited neuromuscular disorders. Typically characterised by impaired oxidative phosphorylation function, they can cause a wide variety of syndromes that can present at any age. The severity of these syndromes ranges from being almost asymptomatic to causing death, with children typically being severely affected. Unfortunately, there are currently no effective treatments for mitochondrial disease. This project aims to improve the search for mitochondrial disease treatments by developing new and innovative screening techniques for use in mitochondrial drug discovery.  

The project

One of the main difficulties in developing new drug discovery assays is the identification of a clear difference between patient and wildtype cells. Typically, there are no obvious differences between the cells of patients with mitochondrial disease and cells with normal mitochondrial function, thus the development of effective screens is difficult. 

Using cell lines donated by patients and healthy volunteers, the student will develop cell painting techniques to stain multiple sub-cellular compartments (mitochondria, cytoskeleton, nucleus, endoplasmic reticulum etc) and image using high-throughput fluorescence microscopy. Supported by Prof Obara, the student will develop image analysis pipelines to quantify the morphology, texture and staining intensity of each sub-cellular compartment and their relationship with each other. This data will be used to build a profile for each cell in order to understand which combinations of parameters are different between patient and wildtype cells. 

In the second part of the project, the student will perform a high-throughput drug screen to discover compounds that revert the profile of patient cells to a wildtype like staining pattern, thus finding compounds that correct the mitochondrial disease phenotype. Secondary screens such as Seahorse oxygraphy will be performed to confirm the activity of the compound(s) and they will work with medicinal chemists to improve the efficacy of the compounds.  

The student will be provided with extensive training in cell culture, microscopy, image analyse and drug screening. They will also be encouraged to participate in a wider programme of mitochondrial biology training to broaden their knowledge of basic and clinical mitochondrial biology. The student will also be able to participate in public and engagement activities, supported by our engagement officer. 

Research Environment

The student will be based primarily in the Wellcome Centre for Mitochondrial Research, with time also spent in the lab of Prof. Obara (Newcastle University). The Wellcome Centre is a vibrant research environment bringing together basic, translational and clinical mitochondrial disease researchers. The Centre boasts a large number of PhD students, providing a supportive and sociable environment to work in. 

Please contact oliver.russell@ncl.ac.uk for further information

For more information about the Centre: 

https://www.newcastle-mitochondria.com/

Dr Oliver Russell’s group:

https://www.newcastle-mitochondria.com/wp-content/cache/all/oliver-russell/index.html

Prof Boguslaw Obara:

http://boguslawobara.com/

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A