The prevalence of type 2 diabetes has risen dramatically during recent decades and there is an urgent need to develop new approaches for disease treatment. Approaches to counteract defective insulin secretion and low beta cell mass in diabetes are key in developing therapeutic strategies. In recent years, therapies that target the actions of glucagon-like peptide-1 (GLP-1) which stimulate insulin secretion through activation of beta cell G-protein coupled receptors (GPCRs) have been successful. This has resulted in substantial interest in targeting other islet GPCRs for diabetic therapies [1-3].
There is an increasing need for new pharmaceutical therapies which preserve beta cell function, decrease weight gain and represent a low risk of hypoglycaemia in diabetes treatment. GPCRs have become the target of approximately 50% of recently developed pharmaceutical agents. Our published work demonstrates that GPCRs activated by endogenous and synthetic agonists in islets, are co-localised with insulin on islet beta cells, and exhibit insulinotropic and glucose lowering activity [4-8]. This research project represents an important step in the validation of these islet targets for improved diabetes treatment and care. This studentship will investigate the biological activation of two GPCRs as therapeutic targets for type 2 diabetes treatment. The multi-faceted research expertise and vision of the Diabetes Research Group coupled with a highly productive team of internationally recognized scientists offers a strong foundation for studentship training.
This research project provides an excellent research training opportunity and represents an important step in the validation of GPCR targets for improved diabetes treatment. The specific project aims:
(i)To determine the functional role of novel GPCRs in the regulation of insulin and glucagon secretion using the clonal pancreatic beta cell line and alpha glucagon secreting cell line; (Milestones: 0-6 months)
(ii)To investigate the mechanism of action and intracellular signalling events activated by islet GPCRs and determine their role in the regulation of cellular proliferation and islet cell mass; (Milestones: 0-12 months)
(iii)To explore the response to activation of GPCR receptors expressed in intestinal cells using GLUTag (GLP-1 secreting) cell line, pGIPneo STC-1 (GIP secreting) cell line, and primary intestinal tissues; (Milestones: 12-24 months)
(iv)To investigate gene knockout of GPCRs in BRIN-BD11 cells using CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats) gene editing tool; (Milestones 14-24 months)
(v)To determine the effects of GPCR agonist monotherapy and combination therapies with other established diabetic therapies such as dipeptidyl-peptidase-IV (DPP-IV) inhibitors in vivo (Milestones 24-36 months).
References:
1.Moran BM, Flatt PR, McKillop AM. (2016) Acta Diabetol. 53(2):177-88
2.Moran BM, McKillop AM, O'Harte FPM. (2016). Curr Opin Pharmacol. 31:57-62.
3.Ahren B. (2009). Nature Reviews 8: 369-385.
4.McKillop AM, Moran BM, Abdel-Wahab YH, Flatt PR. (2013). Br J Pharmacol 170(5):978-90.
5.McKillop AM, Moran BM, Abdel-Wahab YH, Gormley NM, Flatt PR. (2016) Diabetologia 59(12):2674-2685.
6.Moran BM, Abdel-Wahab YH, Flatt PR, McKillop AM. (2014). Biological Chemistry 395:453-64.
7.Moran BM, Abdel-Wahab YH, Flatt PR, McKillop AM. (2014). Diabetes Obes Metab. 16:1128-39.
8.Moran BM, Abdel-Wahab YH, Vasu S, Flatt PR, McKillop AM. (2016) Acta Diabetol 53(2):279-93.
Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.
We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.
In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.
If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.
The University offers the following levels of support:
The following scholarship options are available to applicants worldwide:
These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.
Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.
Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.
The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).
This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.
Due consideration should be given to financing your studies. Further information on cost of living
Submission deadline
Monday 19 February 2018
12:00AM
Interview Date
6, 7 and 8 March 2018
Preferred student start date
Mid September 2018
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