EASTBIO: The many actions of RAR receptor ligands to protect against neurodegeneration – control of neuroinflammation, the blood brain barrier and the potential connection with gut microbiota

This fully funded, 4-year PhD project is part of a competition and is funded by the BBSRC EASTBIO Doctoral Training Partnership and Nevrargenics Ltd.

The enormous influence the gut microbiome has on our body in health and disease has only been recently understood, and that its communication with the CNS via the gut-brain axis means the brain is an integral part of this network. Strong evidence from animal models places gut microbes as pivotal in neurodegenerative diseases, and a significant route by which this comes about is the gut-derived inflammatory response generating neuroinflammation and which may include an influence on the blood brain barrier (BBB). Several targets proposed for the treatment of neurogenerative diseases, such as the retinoic acid receptors (RARs) have been suggested to have their action via these routes, supressing neuroinflammation, regulating the BBB and modulating the gut microbiota.

This project will focus on determining the importance of inflammation, the BBB and the gut microbiome on the action of RAR ligands as treatments for neurodegenerative disorders, with a focus on motor neuron disease (MND). This area has been little explored but holds great promise in determining the key pathways involved in the neuroprotective action of RAR ligands, opening new ways to use these as drugs to treat neurodegenerative disorders such as MND. 

This studentship project is collaborative between world leaders in design of novel ligands for the retinoic acid receptors, based at Durham University, and in the neurobiology of retinoic acid function, and gut microbiome at the University of Aberdeen. In the Department of Chemistry at Durham University the student will work for up to 18 months with Professors Whiting and Pohl on the shape, molecular properties and receptor affinities of newly designed retinoic acid receptor ligands employing novel mathematical modelling tools in this design. This will be correlated in Aberdeen, with Professor McCaffery determining their bioactivity in neural cells and their ability to suppress neuroinflammation in brain and also Dr Indrani Mukhopadhya who will work to determine the role of the gut microbiota in this action. The biological results will feedback to further refine and optimise chemical design of the ligands and their targets.  Thus, the project is highly interdisciplinary, and the student will be taught a wide variety of techniques that include a variety of bioassays for retinoid activity including transcriptional activity and non-genomic signalling. The function of the retinoic acid receptors (RARs and RXRs) will be studied in-depth by methods including siRNA and CRISPR/Cas9 knockdown as well as transgenic animal models.

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ELIGIBILITY:

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.

All students must meet the eligibility criteria as outlined in the UKRI guidance on funding for postgraduate training and development. This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions.

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APPLICATION PROCEUDRE:

• Please visit this page for full application information: How to apply eastbio (eastscotbiodtp.ac.uk)
• Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [email protected]
• Two references should be provided by the deadline using the EASTBIO reference form. References should be sent to [email protected]
• Unfortunately, due to workload constraints, we cannot consider incomplete applications.
• CV’s submitted directly through a FindAPhD enquiry WILL NOT be considered.
• If you require any additional assistance in submitting your application or have any queries about the application process, please don’t hesitate to contact us at [email protected]