PhD Opportunity

*Eastbio*: Serum albumin glycation and its impact on Zn2+-dependent haemostasis and insulin dynamics

University of St Andrews

Dr Alan Stewart & Dr Carlos Penedo

Deadline: 16th December 2021

Project description

Zinc is an essential micronutrient in mammals, vital to virtually all physiological pathways and processes. High nanomolar concentrations of free zinc ions (Zn2+) are cytotoxic; therefore, extracellular zinc is usually well-buffered. The blood is central to systemic distribution of zinc, and here, zinc buffering and transport is overwhelmingly performed by serum albumin.

In blood, Zn2+ also plays a central role in controlling haemostatic functioning. It is released from injured cells and activated platelets where it enhances platelet aggregation, accelerates fibrin clotting and delays clot lysis. Also given that the concentration of free/labile Zn2+ in plasma influences both the quantity and distribution of Zn2+ in platelets, chronic changes in the concentration of available plasma Zn2+ will influence haemostasis. One such disorder in which this can occur is diabetes (both types 1 and 2), in which hypercoagulability and increased risk of thrombosis is frequently observed. It is known that pathophysiological levels of glucose associated with diabetes lead to increased albumin glycation, which has recently been reported to reduce the affinity of Zn2+-albumin binding (Iqbal et al. 2018 J. Biol. Inorg. Chem. 23:447-458). This in turn, may influence Zn2+-dependent coagulation and contribute to the thrombotic complications observed in diabetes.

Furthermore, insulin is stored inside pancreatic β-cells in an inactive Zn2+-bound hexameric form (Zn2Ins6). Upon immediate release, insulin is in the Zn2Ins6 form and only becomes active once Zn2+ disengages from the complex, a necessary step in insulin activation. There are indications that albumin controls insulin signalling by promoting the dissociation of inactive Zn2Ins6 into active monomer through sequestration of Zn2+ (Pertusa et al. 2017. PLoS One 12:e0187547). A process that may be perturbed by glycation and a consequent reduction in the affinity of Zn2+ toward albumin, contributing to altered insulin signalling.

Hypothesis: The primary hypothesis underlying this doctoral project is that HSA glycation affects the zinc binding properties of albumin in a manner that affects both haemostasis and insulin signalling. The specific objectives of this project are therefore to:

  1. Characterise the zinc binding and structural properties of differently glycated albumin using biophysical approaches (e.g. ITC and mass spectrometry).
  2. Examine the effect of glycation on fibrin clot formation parameters using functional assays and microscopic approaches.
  3. Examine the effect of glycation on insulin hexamer breakdown using state-of-the-art fluorescent methods.

Collectively, this work will shed light on how albumin glycation influences Zn2+-albumin interactions and in turn, how it influences haemostasis and insulin dynamics.

Funding

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership- http://www.eastscotbiodtp.ac.uk/how-apply-0.

This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition fees. For international candidates, the University of St Andrews will cover the Home-International fee difference.

How to apply

Application instructions can be found on the EASTBIO website- http://www.eastscotbiodtp.ac.uk/how-apply-0

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 the 16th December 2021.

 

Contact

Queries on the project can be directed to the project supervisor, Alan Stewart

(ajs21@st-andrews.ac.uk)

Queries on the application process can be directed to Rachel Horn (pgmed@st-andrews.ac.uk)

Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions