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EASTBIO: Investigating the biological function of liver HSD17B13 in lipid droplet biology


   School of Medicine, Medical Sciences & Nutrition

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  Dr Nimesh Mody, Dr J Rochford, Prof Julian Griffin, Prof Gopal Sapkota  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

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

The liver is a vital organ that has a wide range of functions, including a critical role in the adaptive response to dietary challenge and physiological state via alterations in metabolism pathways e.g. regulation of glucose and lipid homeostasis. However, fatty liver is a common complication associated with obesity and requires further knowledge and drug discovery for targeting therapeutically. Several studies including human SNP/GWAS, multi-omics data analysis and our own liver RNA-sequencing studies have identified a network of genes that are key drivers of liver lipid homeostasis and metabolic dysfunction (Morrice 2017, Krishnan 2018). Some of these genes have been characterised as encoding proteins involved in lipid metabolism pathways including regulation of lipid droplets e.g. HSD17B13; however most of these proteins have relatively unknown biological functions (Dong 2020).

 Our data leading to a new hypothesis - we now have results that show specifically knocking down liver HSD17B13 leads to amelioration of the excess hepatic triglyceride storage thus providing definitive proof-of-concept evidence that this protein has an important biological function in lipid metabolism. The aim of this project will be to use state-of-the-art techniques to identify the unknown biological function/activity of this novel liver protein. First, you will identify the protein components of the lipid droplet co-localised with HSD17B13 in cells by utilising proximity-based labelling approaches. You will use confocal microscopy to determine the localisation of HSD17B13 and regulation of lipid droplet size in cells in response to lipogenic signalling networks. Functional relevance of variants and mutants of HSD17B13 will be determined similarly. You will perform lipidomics using mass spectrometry with altered HSD17B13 protein levels in cells and liver tissue from mice to identify the unknown activity of this hydroxysteroid dehydrogenase enzyme.

These studies aim to identify the unknown biological function/activity of this relatively novel hydroxysteroid dehydrogenase enzyme and may lead to the identification of a new clinically relevant biomarker for fatty liver. Since HSD17B13 inhibitors are in human clinical trials it is vitally important to identify a specific biomarker of HSD17B13 enzymatic activity to track the progress of these trials. Overall, these studies will delineate a novel biological function of a liver protein involved in hepatic physiology and lipid metabolism and identify a novel physiological pathway to assist with drug discovery and clinical treatment of fatty liver associated with obesity.

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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 UK, EU and international candidates. This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions, esp. TGC 5.2 & Annex B.

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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 Address Removed]
  • Two references should be provided by the deadline using the EASTBIO reference form. References should be sent to [Email Address Removed]
  • Unfortunately, due to workload constraints, we cannot consider incomplete applications.
  • CV's submitted directly through a FindAPhD enquiry WILL NOT be considered.

Funding Notes

This fully funded, 4-year PhD project is part of a competition funded by the EASTBIO BBSRC Doctoral Training Partnership.
This opportunity is open to UK and International students (The proportion of international students appointed through the EASTBIO DTP is capped at 30% by UKRI BBSRC).
EASTBIO studentships includes a UKRI doctoral stipend (estimated at £17,668 for the 2023/2024 academic year), plus a training grant of £5,000 per annum (year 1-3; £1,500 year 4) and a travel/conference grant of £230 per annum.
EASTBIO does not provide funding to cover visa and associated healthcare surcharges for international students.

References

Krishnan, KC. (2018) doi: 10.1016/j.cels.2017.12.006 ;
Morrice, N. (2017) doi: 10.1038/srep43782 ;
Dong XC. (2020) doi: 10.1194/jlr.C120001160 .
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