PhD Studentship - Investigation of the molecular mechanisms underlying antibody-stimulated INSR signaling bias and potential implications for understanding processes linking insulin resistance and development of atherosclerosis

RVC Supervisor(s): Dr Matthew Gage, Professor Caroline Wheeler-Jones

Lead RVC Supervisor: Dr. Gemma Brierley

Department: Comparative Biomedical Sciences

Background, aims and objectives:

One focus of the Brierley lab is the investigation of the potential utility of agonistic INSR antibodies as a therapy for severe insulin resistance caused by INSR mutations. Our studies have shown that these antibodies activate genetically damaged receptors to lower blood glucose in mice and reduce compensatory hyperinsulinemia. Importantly, for what would be a life-long treatment, the agonistic INSR antibodies were found to preferentially activate the PI3K metabolic signalling pathway downstream of the INSR without activating the mitogenic MAPK signalling pathway. This biased signalling elicited by antibody-activated INSR thereby provides a research tool to determine whether the metabolic and mitogenic actions of insulin can indeed be delineated. Understanding these processes will help determine the underlying mechanisms between insulin resistance and the development and progression of cardiovascular disease, the major co-morbidity that inflicts people living with diabetes. Preliminary proteomics studies have revealed antibody-activated INSR preferentially associate with two other cell surface receptors. This PhD studentship research project will aim to define the nature of these receptor interactions, whether they are responsible for the signalling bias towards the PI3K pathway and begin to postulate as to what implications this may have for the pathogenesis of atherosclerosis in people living with insulin resistance and diabetes.

References

  1. Brierley GV, Siddle K, Semple RK. (2018) Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models. Diabetologia. 61(7):1662-1675
  2. Brierley GV, Webber H, Rasijeff E, Grocott S, Siddle K, Semple RK. (2020) Anti-insulin receptor antibodies improve hyperglycemia in a mouse model of human insulin receptoropathy. Diabetes. 69(11):2481-2489
  3. Brierley GV, Semple RK. (2021) Insulin at 100 years – is rebalancing its action key to fighting obesity-related disease? Dis. Model. Mech. 14(11):dmm049340.

Requirements

Essential:

  • A first-class degree in Biomedical science, or similar field
  • Enthusiastic, curious and flexible approach
  • A desire to undertake robust and rigorous research in line with best practices for research integrity
  • Good level of English literacy, numeracy, and experience of using computers to enter and organise data.

Desirable:

  • Higher research degree, such as MSc
  • Previous research experience
  • Knowledge of research methods and design
  • Ability to critically analyse data/information Ability to communicate effectively and work well with others

Fees and Funding

This is a 3-year fully-funded studentship, funded by the RVC internal studentship award. This funding covers 'Home' rate tuition fees and a stipend. 

The studentship will commence in October 2025 at the RVC's Camden campus.

This studentship is open to applicants eligible for "Home" fees. International applicants are welcome to apply but must be able to fund the difference between "Home" and "Overseas" tuition fees. 

EU/EEA and Swiss national students starting studies in the 2021/22 academic year or later academic years may no longer be eligible to pay the “home” rate of tuition fees nor claim any financial support for their studies dependent on your personal circumstances (including immigration status and residence history in the UK). To help determine whether you would be eligible for home fees please see the UKCISA's 'Who pays 'home' fees for higher education in England?' guide found here.

If you are interested in applying for this PhD project, please follow the link below.  Please use your personal statement to demonstrate any previous skills or experience you have in using both qualitative and quantitative research methods.

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Interviews are expected to take place in person at our Camden campus or remotely in March 2025 (date TBC). 

We welcome informal enquiries - these should be directed to Dr Gemma Brierley (Lead Supervisor): gbrierley@rvc.ac.uk

Deadline: 12/02/2025

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