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Investigating the cell biology mechanisms activated by bile acids and metabolites in Parkinson’s disease patient cells


   Department of Neuroscience

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  Dr Heather Mortiboys  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Parkinson’s disease is the second most common neurodegenerative disease, with prevalence increasing. To date there is only symptomatic treatment, with no treatment, which slows or stops disease progression. There are several cellular pathways, which are thought to be involved in the cell death leading to the development of Parkinson’s symptoms; these include mitochondrial dysfunction, abnormalities of the ubiquitin proteasome system and the lysosomal system, oxidative stress and neuroinflammation. Increasing evidence suggests a restorative effect of bile acids in Parkinson’s, with the discovery ursodeoxycholic acid (UDCA) restores several of the above mentioned pathways. UDCA is in currently in clinical trials for Parkinson’s. In addition, alterations have been found in the bile acid profile in Parkinson’s patient samples. Bile acids are naturally occurring; the number of metabolites and modifications made to naturally occurring and synthetic bile acids is huge.

We have (Mortiboys and Bandmann Labs) extensively investigated a range of mitochondrial restoration effects of both naturally occurring and synthetic bile acids (synthesised by our industrial partner, NZP UK Ltd) in Parkinson’s patient fibroblasts and reprogrammed iDopaminergic neurons. This work has revealed a novel mechanism by which some bile acid compounds can modulate mitochondrial function.

The current project aims to further elucidate the cellular mechanisms, which are activated by the multitude of metabolites of these naturally occurring and synthetic bile acids. This work is critical in understanding the active compound eliciting any beneficial neuronal restorative effects for Parkinson’s Disease. You will undertake the work in samples from patients with both familial and sporadic Parkinson’s Disease; these samples are all readily available in the laboratories of the supervisors. You will use state of the art reprogramming and differentiation techniques to investigate the pathways activated by bile acid metabolites. These will include hormone receptor activation, apoptotic cell death pathways, PI3K activation pathways and mitochondrial functional pathways including membrane integrity, oxidative phosphorylation function, mitochondrial DNA content, fatty acid oxidation and lipid metabolism. The effect of various bile acid metabolites will also be assessed on neuronal viability and health in mono culture and in co-culture with astrocytes.

The successful student will work closely together with a multidisciplinary team of researchers including biologists, neurologists and chemists from academia and industry to ultimately advance our understanding of the beneficial and toxic effects which are elicited by bile acid treatment allowing us to fully understand their neuroprotective therapeutic potential for Parkinson’s Disease and other neurodegenerative conditions.

Funding:

This studentship will be 42 months in duration and include home fee and stipend at UKRI rate. EU/Overseas candidates are welcome to apply, however they would be required to fund the fee difference.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience.

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Neuroscience' as the department. Please also state your first and second choice project by entering the project tiles in the 'Research Topic' box on your application.

Enquiries:

Interested candidates should in the first instance contact Dr Heather Mortiboys [Email Address Removed]

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