PhD Study : Islet peptides and paracrine interactions in the physiological and dysfunctional regulation of islet hormone secretions

Summary

Islets of Langerhans are individual clusters of heterogenous cell types responsible for the secretion of insulin, glucagon and somatostatin plus an increasing number of unsuspected brain-gut peptides. Each cell type is regulated in a different manner by glucose, other nutrients and circulating factors. However, intra-islet autocrine or paracrine effects, whereby the secretory products of the islet cells affect secretory activity of surrounding cells, are likely to play an important role in both islet physiology and pathology in diabetes.

For example, the well-known ability of glucagon-like peptide-1 (GLP-1) secreted by intestinal L-cells to inhibit glucagon secretion is not mediated by a direct action on alpha cells but via stimulation of somatostatin release from adjacent delta cells which in turn inhibits glucagon secretion. Such paracrine actions together with influence of autonomic nerves, nutrients and various circulating hormones normally interact to regulate insulin secretion and islet cell function, thereby ensuring tight control of glucose homeostasis.

In addition to insulin, glucagon and somatostatin, we have recently demonstrated that the islet cells contain a surprising number of non-classical islet peptides. This heterogeneity is not confined to but is particularly marked in alpha cells. These non-classical peptides include brain-gut hormones such as gastric inhibitory polypeptide (GIP), GLP-1, oxyntomodulin, GLP-2, peptide YY (PYY), cholecystokinin (CCK), gastrin, xenin, oxytocin and vasopressin.

These potentially important paracrine factors are co-localized with the classical islet peptides, possibly within distinct secretory granules, and when secreted may have a disproportionately large regulatory effect on insulin, glucagon or somatostatin secretion due to their high local concentration within the islet interstitial space and vasculature.

Core objectives of the proposed research are:

1. Determine the presence, precise chemical structure and cellular location of non-classical islet peptides in the pancreatic islets of normal and diabetic animals.
2. Examine the kinetics of their release from perfused pancreas in relation to the output of insulin, glucagon and somatostatin.
3. Evaluate the actions of natural physiological stimulators and drugs on islet cell secretions plus the effects of known peptide receptor inhibitors
4. Dissect the involvement of islet cell interactions in the overall regulation of islet function in normal physiology and animal models of diabetes.

This project will involve techniques such as immunocytochemistry, tissue culture, cell incubations, small animal handling and experimentation, pancreas perfusion, islet isolation, PCR, gene silencing, fluorometric assay, radioimmunoassay, HPLC, MALDI-TOF and MSI. In addition, PCR and Western blotting will be utilised to explore gene and protein expression of key elements of signal transduction pathways plus cellular interactions between various islet cells (such as connexin 43, connexin 36, E-cadherin). The proposed project will provide experience of cutting-edge research and afford comprehensive training in a wide range of in vitro and in vivo techniques.

A background in biology, biomedical sciences, nutrition, pharmacology or related subject would be desirable.

Applicants should note that Laboratory bench fees of £6,000.00 per annum are required for this self-funded PhD 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