PhD Study : ​​Elucidating the role of kisspeptin and related peptide analogues on beta cell function and survival ​​

Summary

​Kisspeptin is a 54 amino acid hypothalamic peptide hormone that activates G protein-coupled KISS1 receptors. However, the physiological function of kisspeptin is not confined to the hypothalamus, as the hormone and its receptor are abundantly expressed in various tissues, including the endocrine pancreas. Kisspeptin has been shown to stimulate insulin secretion from beta cells. Further to this, there is knowledge that kisspeptin can affect cell survival and proliferation. Whether this extends to survival and proliferation of pancreatic beta-cells, with obvious beneficial effects for diabetes, remains to be elucidated. However, as with many peptide hormones, kisspeptin is proteolytically processed into several smaller fragments. Uncovering the mechanisms involved in kisspeptin degradation, its role in diabetes progression together with direct effects of kisspeptin and related fragments on beta-cell function and survival could help reveal, an as yet untapped, therapeutic strategy for treatment of diabetes.

Therefore, the following research questions will be addressed: What impact do kisspeptin peptides have on pancreatic beta-cell function? Kisspeptin is known to be proteolytically processed into several smaller fragments composed of 10, 13 and 14 aa. Initially we will determine full enzymatic degradation profile of kisspeptin and assess secretory and functional effects of kisspeptin peptides on rodent and human insulin-releasing cell lines as well as isolated murine islets. How does the islet peptidome alter with respect to kisspeptin peptides in response to metabolic stress? Changes in islet peptidome following induction of diabetes through dietary-, chemical- or genetic-interventions will be studied in mice. As such, we will employ high fat feeding, STZ injection or obese-diabetic mice with appropriate controls. A peptidomic approach will be utilised to specifically examine changes in islet kisspeptin peptides during diabetes development. Whole islets and fluorescent-activated cell sorted islet alpha- and beta-cells will be analysed. Pregnant female mice will also be employed, as pregnancy is also known to exert important adaptive effects on islets in response to stress. What impact will enzymatically stable kisspeptin peptides have on metabolic control in diabetes?

Using knowledge gained from Aims 1&2, alongside established peptide chemistry expertise, we will synthesise long-acting stable kisspeptin analogues. Preclinical therapeutic effectiveness of lead kisspeptin peptides will be studied in models of diabetes. We will also examine benefits and additive effects of combined therapy with clinically approved antidiabetic agents.

Expected Results:

Based on the literature, kisspeptin and related peptides will impact beta-cell function. We expect to observe positive effects on insulin secretion as well as beta-cell growth and survival. Metabolic stress induced by development of diabetes, or through pregnancy, alters the islet peptidome and we are confident that signature changes in kisspeptin peptides are important in this process. These studies will add to our understanding of how kisspeptin and KISS1 receptor activation modulate islet function and control of metabolism. Long-acting kisspeptin peptide analogues should be able to reproduce sustained benefits of KISS1 receptor activation on islets for potential therapeutic application in diabetes.

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.

Essential criteria

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.

• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Clearly defined research proposal detailing background, research questions, aims and methodology

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Experience using research methods or other approaches relevant to the subject domain
• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Work experience relevant to the proposed project
• Publications record appropriate to career stage
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

• Full Award: (full-time tuition fees + £19,000 (tbc))
• Part Award: (full-time tuition fees + £9,500)
• Fees Only Award: (full-time tuition fees)

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.

Department for the Economy (DFE)

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.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• 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.

Due consideration should be given to financing your studies. Further information on cost of living