Principal Supervisor:        Claire Thornton

Co-Supervisor:       Irilenia Nobeli

Project Description

Mitochondria need to work efficiently in order to meet our cellular energy requirements especially in energy-demanding organs such as the brain. Mitochondrial dysfunction is a key hallmark of neonatal hypoxic-ischaemic encephalopathy (HIE), a brain injury that occurs in response to asphyxia during birth. HIE results in life-changing neurological consequences for 1-2 in every 1000 term babies in the UK, and significantly more in low resource countries; currently there are limited treatment options.   We previously identified the mitochondrial pro-fusion protein OPA1 as a target in a mouse model of neonatal hypoxic-ischaemic (HI) injury. Exposure to HI results in impaired ATP production, OPA1 cleavage and increased mitochondrial fragmentation. The aim of this PhD project will be to determine the impact of OPA1 degradation on protein interactions, cell survival and metabolic pathways in glial cells in order to devise strategies to protect OPA1 function and minimise brain injury.   To achieve this aim, you will generate RNA-seq/metabolomics datasets from glial cells and determine the molecular and metabolic pathways altered in response to OPA1 impairment, using a variety of in vitro, ex vivo and in silico techniques. In addition, you will develop and use computational modelling skills to identify small molecule ligands/drugs as candidates to maintain OPA1 function.   Safeguarding the integrity and function of OPA1 following hypoxia-ischaemia may represent a new mechanism to prevent the development of neonatal brain injury. Interventions based on maintaining OPA1 activity may provide additional neuroprotection for infants following birth asphyxia.

Subject Areas/Keywords

Cell Biology, Computational modelling   Mitochondria, neonatal, hypoxic-ischaemia, RNASeq, molecular docking, brain

Key References

Baburamani AA, Hurling C, Stolp H, Sobotka K, Gressens P, Hagberg H and Thornton C (2015) Mitochondrial Optic Atrophy (OPA)1 processing is altered in response to neonatal hypoxic- ischaemic brain injury. Intl J Mol Sci 16, 22509-22526 doi: 10.3390/ijms160922509   Thornton C, Jones A, Nair S, Aabdien A, Mallard C and Hagberg H. (2018) Mitochondrial dynamics, mitophagy and biogenesis in neonatal hypoxic ischaemic brain injury FEBS Letters 592(5):812-830 doi: 10.1002/1873-3468.12943   Li, D., Wang, J., Jin, Z., & Zhang, Z. (2019). Structural and evolutionary characteristics of dynamin-related GTPase OPA1. PeerJ, 7, e7285 doi: 10.7717/peerj.7285

Further details about the project may be obtained from

Principal Supervisor:        Claire Thornton: cthornton@rvc.ac.uk

Co-Supervisor:       Irilenia Nobeli: i.nobeli@bbk.ac.uk

Further information about PhDs at the RVC is available from

https://www.rvc.ac.uk/study/postgraduate/phd

Application forms and details about how to apply are available from

https://www.rvc.ac.uk/study/postgraduate/phd/how-to-apply

 If you are interested in applying for this position, please follow the link above to submit your application and CV.  Please use your personal statement to demonstrate any previous skills or experience you have in mitochondrial/glial cell biology and/or bioinformatics/computational modelling.

Candidates will be shortlisted at the end of February and interviews are anticipated to be held via Zoom from mid-March onwards.