PhD Opportunity – EASTBIO: Role of Glutamine Synthetase in Insulin and Glucagon Secretion and the Metabolic Crosstalk Between β- and α-Cells
Project Title:
EASTBIO: Role of Glutamine Synthetase in Insulin and Glucagon Secretion and the Metabolic Crosstalk Between β- and α-Cells
Supervisor(s):
Principal Supervisor: Dr. Victor Hugo Villar Cortes (School of Medicine), [email protected].
Co-supervisor: Dr. Alan Stewart (School of Medicine), [email protected].
Deadline:
Friday 17 January 2025
Project Description:
Glutamine synthetase (GS) is the only enzyme that synthesizes glutamine from ammonia and glutamate. This enzyme is essential for organ-specific functions, particularly in the liver and brain where it plays a crucial role in ammonia detoxification and controlling glutamate levels respectively. Thus, the dysregulation of GS activity has been implicated in diseases such as diabetes, cancer, and obesity. The islets of Langerhans are specialized pancreatic structures that regulate systemic glucose levels. These islets are composed by distinct cell types, including β-cells, which produce insulin and α-cells, which secretes glucagon, hormones that decrease and increase blood glucose levels respectively. Although GS is expressed in islets, its role in the secretion of insulin or glucagon remains elusive.
This PhD project aims to elucidate the normal metabolic role of GS on insulin and glucagon secretion and explore the metabolic connection between β and α-cells using in vitro models.
Objective 1: Metabolic role of GS in the secretion of insulin. We will use cellular models of β-cells (Min-6, INS1E, EndoC-βH1), genetic approaches (CRISPR/Cas9, overexpression), pharmacological approaches, stable isotope tracing (13C6-glucose), oxygen consumption (Seahorse) and metabolomics approaches (LC-MS/MS) to dissect the metabolic role of GS on insulin secretion. Untargeted metabolomics approaches will also allow the identification of novel metabolic regulators of insulin secretion.
Objective 2: Metabolic role of GS in the secretion of Glucagon. We also aim to understand the metabolic role of GS in the secretion of glucagon in α-cells models (α-TC-1 cells) using the same approach described in objective 1.
Objective 3: Exploring the metabolic crosstalk between β-cells and α-cells in pseudo-islets.
The metabolic crosstalk between α-cells and β-cell and its relevance on the secretion of insulin or glucagon remains unclear. We will use pseudo-islets formed by α-cells (α-TC-1), β-cell (INS1E) with different GS expression and endothelial cells (HUVEC) to generate different types of pseudo-islets. We will interrogate these different pseudo-islets using targeted/untargeted LC-MS metabolomics to identify metabolite that correlate with the secretion of insulin and glucagon. In addition, we will use DESI-MSI (Desorption Electrospray Ionization Mass Spectrometry Imaging) to define the special distribution of metabolites within the pseudo-islets and correlate its levels with marker of α-cell and β-cells using immunohistochemistry (IHC). This integrated approach aims to uncover novel insights to understand the metabolic role of GS in β- and α-cells, and the secretion of insulin and glucagon. These findings could offer valuable perspectives on the metabolic regulation of pancreatic hormone secretion.
Funding Details:
This 4-year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership.
This opportunity is open to UK and International students and provides funding to cover stipend at UKRI standard rate and UK level tuition fees. The University of St Andrews will cover the Home-International fee difference.
How to Apply:
Application instructions can be found on the EASTBIO website – https://biology.ed.ac.uk/eastbio/how-to-apply.
1) Download and complete the Equality, Diversity and Inclusion survey.
2) Download and complete the EASTBIO Application Form.
3) Submit an application to St Andrews University through the Online Application Portal.
Your online application must include the following documents:
- Completed EASTBIO application form.
- 2 References (to be completed on the EASTBIO Reference Form, also found on the EASTBIO website).
- Academic Qualifications.
- English Language Qualification (if applicable).
Unfortunately, due to workload constraints, we cannot consider incomplete applications. Please make sure your application is complete by 17th January 2025.
Contact:
Queries on the project can be directed to the project supervisor.
Queries on the application process can be directed to Rachel Horn at [email protected].
UKRI eligibility guidance: Terms and Conditions: View Website International/EU: View Website.