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Understanding how glucagon-like peptide-1 (GLP1) and gastric inhibitory polypeptide (GIP) receptors contribute to metabolism in complex tissues.


   Radcliffe Department of Medicine

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  Prof D Hodson  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Our labs are focused on developing and using novel technologies to address challenging problems in cellular metabolism, with translational relevance for patients. We have particular interest in glucagon-like peptide-1 (GLP1) and gastric inhibitory polypeptide (GIP) receptors, two related class B G protein-coupled receptors. Both receptors are involved in the regulation of glucose homeostasis, food intake and inflammation and as such have become blockbuster drug targets. For example, stabilised GLP1 receptor agonists are used in the treatment of type 2 diabetes, have just been approved as the first non-surgical treatment of obesity, and have shown promise for the treatment of fatty liver disease, as well as neurodegenerative disease. While GIP receptors have gained less interest, recent studies have shown that agonists targeting both GIP receptors and GLP receptors have highly synergistic actions to lower blood glucose levels, as well as food intake. Thus, dual agonists simultaneously targeting both GLP1 and GIP receptors are likely to become the major future drug treatment for metabolic and other diseases. 

Despite this, much remains unknown regarding GLP1 and GIP receptor signalling, let alone how they interact at the cell surface to elicit a synergistic response. Moreover, GLP1 and GIP receptors are low abundance proteins and as such difficult to reliably detect. Over the past decade we have been at the forefront of those trying to understand GLP1 and GIP receptor localization and signalling. To this end, we have used chemical biology to develop a number of fluorescent agonists allowing us to specifically visualize the distribution of GLP1 and GIP receptors in different target tissues. Alongside this, we have generated CRISPR-Cas9 genome-edited mice in which GLP1R and GIP receptors can be precisely interrogated in space and time. Lastly, we have deployed super-resolution imaging to allow single molecule imaging of GLP1 and GIP receptors, revealing their higher order organization. By applying this expertise and technology to the pancreatic islets, brain and liver, we have been able to show: 1) exactly where GLP1 and GIP receptors are located in the body; 2) that their signalling in complex multicellular tissues is heterogeneous; 3) that synergism between GLP1 and GIP receptors leads to sequestration of receptor at the cell surface; and 4) that GLP1 receptors form hotspots, with some cells having very high expression levels. 

We now want to capitalize on this work by understanding exactly how GLP1 and GIP receptors interact in the pancreatic islets, liver and brain to regulate glucose homeostasis and food intake. Using an inter-disciplinary approach, we will combine novel chemical biology probes with mouse models, human tissue and advanced imaging to dissect out how GLP1 receptor agonists, GIP receptor agonists, dual agonists and combinations therein influence signalling, cell function and organismal homeostasis. Relevant preclinical (e.g. high fat diet) will be used throughout and tissue will be sampled from individuals with diabetes, obesity and fatty liver disease. Our overarching goal is to provide novel insight into GLP1 and GIP receptor signalling in complex tissue, and inform the next generation of therapeutics against common metabolic diseases such as diabetes and obesity. 

The labs have an established track record in training and mentoring, with all of our previous postgraduate students going onto positions in academia, industry, consulting or patent law. A number of our students have been awarded local and national prizes for their work. The labs are highly supportive and the lab heads are usually present most days, helping out with and advising on experiments. The labs have an open door policy and no request is too much trouble. Training will be provided in advanced imaging (confocal, two-photon and super-resolution), molecular biology, recombinant genetics, genetically-altered animal work, chemical biology (peptide synthesis/coupling), image analysis and statistical analysis. Training will be provided by the lab heads, as well as senior members of the labs, all with experience in postgraduate student supervision. There will also be opportunity to work closely with collaborators in the UK, Germany and US, with scope for site visits to learn new skills where applicable.

Additional supervision will be provided by Professor Jeremy Tomlinson.

My group will be moving to Oxford in January 2022 and we will be welcoming DPhil students from October 2022. Informal enquiries are welcome and can be directed to David Hodson ([Email Address Removed]).

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.


References

1 Ast et al, ChemRXiv 2021 DOI: 10.33774/chemrxiv-2021-7rngq
2 McLean et al, Endocrine Reviews 2021 DOI: 10.1210/endrev/bnaa032
3 Nasteska et al, Nature Communications 2021 DOI: 10.1038/s41467-020-20632-z
4 Ast et al, Nature Communications 2020 DOI: 10.1038/s41467-020-14309-w
5 Podewin et al, ACS Central Science 2018 DOI: 10.1021/acscentsci.7b00237
6 Armstrong et al, Journal of Hepatology 2016 DOI: 10.1016/j.jhep.2015.08.038

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