About the Project
Supervisors: Prof. Finbarr O’Harte & Dr. Nigel Irwin
Project Description: Apelin is a peptide (adipokine) secreted from adipocytes which activates APJ receptors that are located in multiple tissues. Tatemoto and colleagues discovered that apelin was a selective endogenous ligand for the orphan APJ receptor (Tatemoto et al. 1998). This APJ receptor was found in a number of tissues in rodents and man. Apelin actions include feeding behaviour, glucose utilization and insulin secretion. At Ulster we have developed stable apelin analogues with potent antidiabetic actions comparable to incretin mimetics.
The present proposal aims to test the longer-term efficacy of apelin analogues alone and in combination with incretin mimetic therapies in vitro using various cell culture models, as well as in leptin deficient obese diabetic (ob/ob mice) and to determine their main in vivo mechanisms of action. Development of an assay for an apelin analogue will enable necessary pharmacokinetic studies to be undertaken.
Thus we will fully evaluate the antidiabetic potential of APJ receptor activation using the two most effective analogues (A and B). Both analogues will be tested for their effects on in vitro insulin secretion in BRIN-BD11 cells alone and in combination with incretin mimetics in clinical use. Additional in vitro studies will be undertaken and an MS based assay developed against the most promising analogue for detection of apelin analogue(s) in mouse plasma samples following treatment.
For assessment in vivo control groups of obese hyperglycaemic (ob/ob) mice or heterozygous (ob/+) mice (n=8) will receive twice daily injections of saline or analogues A or B, liraglutide, or the combination of analogue B with liraglutide for 42 days. We will examine functional effects of chronic administration upon food intake, body weight, body composition, energy metabolism, glucose tolerance and insulin sensitivity. Cellular actions on pancreatic islet alpha and beta cells, muscle, adipose, hypothalamus and intestinal enteroendocrine cells will be assessed. The effectiveness of treatments upon cardiovascular outcomes and lipid parameters will be evaluated. The in vivo pharmacokinetic profile will be determined and the expression of key genes of interest in various tissues. Overall this work promises a better understanding of apelin’s mechanisms of action and will help bring forward a new drug target for obesity related diabetes.
Informal enquiries to Prof. O’Harte ([Email Address Removed]) are welcome.
Reference: Tatemoto K, et. al. Biochem Biophys Res Commun. 1998; 251:471–476.
References and additional links
For more information on this project, the supervisory team and graduate studies at Ulster, please visit
http://www.science.ulster.ac.uk/gradschool/biomedical/
How to apply for this project:
http://www.ulster.ac.uk/research-and-innovation/phdresearch-degrees/how-to-apply
Closing date for Applications is 24 February 2017.
Funding Notes
The Department for the Economy (DfE) (formerly called Department for Employment and Learning (DEL))
The University has DfE research studentships available for PhD projects. These pay tuition fees and an annual maintenance award of not less than £14,553 per annum. These awards are open to holders of, or those expected to obtain, first or upper second class honours degrees and cover fees at the home rate and, for applicants with UK residence only, a maintenance allowance. Non-UK residents who hold ordinary EU residence may also apply but, if successful, will receive fees only. Applicants should indicate in the appropriate box on their University application form that they wish to apply for a DfE award. The closing date for receipt of applications will be 24 February 2017. Information on terms and conditions for DfE awards, including eligibility, can be found here: DfE Terms and Conditions for 2016/2017
Vice-Chancellor's Research Scholarships (VCRS)
A number of University funded VCRS will be available for PhD projects at Ulster. These awards are open to applicants who hold or, expect to obtain, a first or upper second class honours degree. They will cover tuition fees and a maintenance award of not less than £14,553 per annum for three years. Applications are invited from UK, European Union and overseas students. Applicants with up to one year’s current or previous registration for PhD at any institution may be considered for an award subject to the applicant providing evidence of good academic progress, formal release from all IP restrictions and ethical approval (if required). Three-year awards may be allocated to such applicants where they are taking-up a new project at Ulster. Applicants should indicate in the appropriate area on their University application form that they wish to apply for a University Studentship/VCRS award. The closing date for receipt of applications will be 24 February 2017. Information on terms and conditions for VCRS awards, including eligibility, can be found here: VCRS Terms and Conditions for 2016/2017
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