Gut hormones are extremely important for controlling energy homeostasis and metabolism, and represent excellent drug targets for diseases such as obesity and diabetes. With increasing levels of obesity giving rise to Type 2 diabetes and polycystic ovary syndrome (PCOS), an increasing number of women of childbearing age are being diagnosed with low grade endometrial cancer. Receptors for the gut hormones GLP-1 and GIP are located in reproductive tissues (pituitary, ovary and uterus) and it has been suggested that analogues of these hormones could prove useful in the treatment of endometrial cancer and in the preservation of fertility in these patients.
As these gut-hormone based drugs work to reduce body weight and improve glycaemic control, this project seeks to uncover the direct and indirect mechanisms underlying the effects of gut-hormone analogues in an animal model of endometrial cancer. At Ulster, we have extensive experience of investigating peptide based therapeutics in the treatment of diabetes, obesity and female infertility.
Using this initial knowledge, the following research questions will be addressed as part of this PhD project: Does treatment with GLP-1 and other gut hormone analogues reduce the incidence of endometrial hyperplasia in rodent models of endometrial cancer. High fat diet and the administration of low dose ethinylestradiol (EE) induces obesity and endometrial cancer in rodents. High fat fed EE treated mice will be administered stable analogues of glucagon-like peptide-1 (GLP-1), GIP and PPY, which each exert independent benefits on body-weight and insulin secretion. Antagonists of these peptides will be administered to elucidate whether the beneficial effects of these hormones is due to weight loss and improved glycaemic control, or whether the effects are due to the direct effects of receptor activation on reproductive tissues.
Our laboratory has already developed bioactive, fully enzymatically stable, versions of these peptides. Will gut-hormone therapies preserve the fertility of rodents with low grade endometrial cancer? Using knowledge gained from Question 1, the gut hormone analogues will be progressed to preclinical therapeutic efficacy trials.
Our laboratory has significant experience in monitoring eostrus cycling and carrying out breeding studies to assess the fertility in obese and diabetic rodent models. What are the mechanisms underlying the beneficial effects of gut hormone therapies in endometrial cancer? A peptidomic approach will be utilised to specifically examine changes in the ovarian, pituitary and uterine peptidome following sustained activation of GLP-1, GIP and NPY receptors in rodent models of endometrial cancer and sub-fertility. Plasma will be collected to measure circulating hormone levels and biomarkers for endometrial cancer. Given the origin and direct effects of GLP-1, GIP and PYY, peptidomic analysis of enteroendocrine cells and pancreatic islets will also be conducted.
Expected Results:
Based on pilot studies we expect to observe likely additive or synergistic benefits of gut-hormone receptor activation on endometrial hyperplasia. Administration enzyme-resistant long-acting GLP-1, GIP and PYY peptides should allow for assessment of this approach as a potential new therapeutic option for endometrial cancer and accompanying infertility, with efficacy equivalent or superior to currently
Please note: Applications for more than one PhD studentships 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.
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
Moffett RC, Naughton V. Emerging role of GIP and related gut hormones in fertility and PCOS.Peptides. 2020 Mar;125:170233.
Kanda R, Hiraike H, Wada-Hiraike O, Ichinose T, Nagasaka K, Sasajima Y, Ryo E, Fujii T, Osuga Y, Ayabe T. Expression of the glucagon-like peptide-1 receptor and its role in regulating autophagy in endometrial cancer. BMC Cancer. 2018 Jun 15;18(1):657.
Gonthier C, Walker F, Luton D, Yazbeck C, Madelenat P, Koskas M. Impact of obesity on the results of fertility-sparing management for atypical hyperplasia and grade 1 endometrial cancer. Gynecol Oncol. 2014 Apr;133(1):33-7.
Kanda, R., Hiraike, H., Wada-Hiraike, O. et al. Expression of the glucagon-like peptide-1 receptor and its role in regulating autophagy in endometrial cancer. BMC Cancer 18, 657 (2018).
Submission deadline
Monday 28 February 2022
12:00AM
Interview Date
April 2022
Preferred student start date
mid September 2022
Telephone
Contact by phone
Email
Contact by email