The prevalence of type 2 diabetes has risen dramatically during recent decades and there is an urgent need to develop new approaches that provide a combination of benefits, with fewer side effects. In recent years, therapies that target GLP-1, which acts through G protein-coupled receptors (GPCRs) have been successful, resulting in substantial interest in targeting other islet GPCRs for diabetic therapies. GPCRs are a superfamily of transmembrane receptors that transduce extracellular signals into intracellular responses. GPCRs are the target of approximately 50% of all recently developed pharmaceutical agents.
Our published research shows that targeting GPCRs such as GPR120 and GPR40 can counteract defective insulin secretion, incretin release, low beta cell mass, insulin resistance and inflammation which are key characteristics of diabetes and CVD. In this project, G protein-signalling cascades will be characterised in islets using precision proteomics, Western blotting, peptide assays, cAMP imaging by fluorescence microscopy and GPCR gene knockout studies using CRISP-R (Clustered regularly interspaced short palindromic repeats) gene editing. The effects of specific GPCR agonist therapy in human studies on the regulation of glucose tolerance, insulin resistance and inflammation will be determined in vivo.
This PhD project represents a significant step in the validation of these islet targets for improved diabetes treatment and care. The project aims to investigate:
(i) The mechanism of action and receptor-mediated intracellular signalling events activated by islet GPCRs and determine their role in the regulation of pancreatic function, cellular proliferation and islet cell mass.
(ii) Gene knockout of GPCRs using CRISP-R gene editing, fluorescence microscopy, mass spectrometry, PCR and western blotting to investigate the common downstream signalling molecules activated in diabetes and cardiovascular disease.
(iii) To evaluate the anti-diabetic and anti-inflammatory effects of GPCR activation by naturally occurring omega-3 and omega-6 polyunsaturated fatty acids in clinical studies in patients with type 2 diabetes.
Please note: Applications for more than one PhD studentship are welcome, however if you apply for more than one PhD project within Biomedical Sciences, your first application on the system will be deemed your first-choice preference and further applications will be ordered based on the sequential time of submission. If you are successfully shortlisted, you will be interviewed only on your first-choice application and ranked accordingly. Those ranked highest will be offered a PhD studentship. In the situation where you are ranked highly and your first-choice project is already allocated to someone who was ranked higher than you, you may be offered your 2nd or 3rd choice project depending on the availability of this project.
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