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Development of novel fluorescent glucose indicators for lungs in vivo imaging


Faculty of Health and Life Science

About the Project

We are looking for a highly motivated student to work with us on an exciting project to develop in fluorescent tools optimised for in vivo imaging and investigate glucose levels in lungs.

The respiratory tract is covered by the airway surface liquid (ASL), a thin layer of fluid that lines the luminal surface of the epithelium and which is important for lung defence against infection. In the upper airway, glucose is normally maintained at a low concentration (0.4 mM, 12.5x less than blood) in order to limit bacterial growth. During respiratory disease or in diabetic patients, blood and ASL glucose levels are elevated. The increase in ASL glucose concentration makes airways more susceptible to pathogen colonisation and associated disease.

Measuring glucose concentrations in airways is challenging because of limited accessibility, the thinness of the ASL and low concentrations of glucose obtained when dilution techniques are used (e.g. brochoalveolar lavage and exhaled breath condensate).

Our group developed and characterised glucose biosensors which allowed less invasive continuous monitoring of plasma glucose in vitro and in cellular models. These biosensors were based on the bacterial glucose/galactose-binding protein (GBP) covalently linked to environmentally sensitive fluorophores. These promising tools however, do not allow real-time monitoring of glucose in vivo.

In this project, we will take an innovative approach to develop novel genetically-encoded glucose indicators that will allow real-time, in vivo monitoring of glucose concentration changes in animal models and human patients. Visualising glucose dynamics in vivo using fluorescent sensors would greatly contribute to understanding ASL glucose homeostasis, how it is changed with inflammation and hyperglycaemia and how it modifies the innate immunity in the ASL.

Based on our track record in developing protein-based fluorescent sensors (for calcium, glutamate and glucose), we aim to create and characterize a unique palette of genetically-encoded glucose indicators. Selected glucose biosensors will be tested in human Calu-3 cells and primary human bronchial epithelial cells (grown on transwell permeable support) to evaluate their potential for in vivo imaging. These experiments will be performed in collaboration with Prof Baines (St George’s, University of London). A fluorescent indicator capable of real-time tracking of glucose concentration changes in vivo will be a valuable tool to better understand airway epithelial glucose homeostasis and predict susceptibility to respiratory infection.

This is an exceptional opportunity for the successful applicant to receive comprehensive research training in techniques ranging from molecular cloning, protein biochemistry, structural biology and cell biology and fluorescence microscopy. The successful applicant will also gain experience in dissemination of scientific knowledge by preparing articles for publication and through presenting findings at both national and international research conferences. In the Institute of Life Course and Medical Sciences (ILCaMS), regular access to journal clubs and weekly meetings will provide valuable exposure to working within a multidisciplinary environment. Broader research training will also be provided through the University’s PGR training programme and doctoral training college.

The student will be supervised by Dr Nordine Helassa, BHF Research Fellow in Cardiovascular Science, Dr Lee Haynes and Dr James Johnson who will provide training and support in all relevant techniques. The project will be hosted in the Department of Cardiovascular and Metabolic Medicine in ILCaMS.

https://www.liverpool.ac.uk/life-course-and-medical-sciences/

We are looking for a highly motivated student who is willing to pursue cutting-edge research within a vibrant and collegiate team. A basic background in protein biochemistry would be beneficial. The ILCaMS is fully committed to promoting and supporting equality, diversity and inclusion. In recruitment, we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

Essential eligibility requirements:

• BSc (minimum 2.1 honours degree) in a related discipline.

• Excellent communication skills.

Enquiries to: Dr Nordine Helassa ()

To apply: Applicants should send a CV and a covering letter (2-page max) anytime before the deadline to Dr Nordine Helassa,

Expected interview date/week: Suitable candidates will be contacted for an interview shortly after applying


Funding Notes

The successful applicant will be expected to provide the funding for tuition fees, living expenses as well as research costs. Details of costs can be found on the University website: View Website. Laboratory bench fees of ~£15,000/year for each of the three years of the project are required.

References

1. Helassa N, Garnett JP, Farrant M, Khan F, Pickup JC, Hahn KM, MacNevin CJ, Tarran R, Baines DL. A novel fluorescent sensor protein for detecting changes in airway surface liquid glucose concentration. Biochem J. 2014 Dec 1;464(2):213-20. doi: 10.1042/BJ20141041. PMID: 25220254; PMCID: PMC4357280.
2. Keller JP, Marvin JS, Lacin H, Lemon WC, Shea J, Kim S, Lee RT, Koyama M, Keller PJ, Looger LL. In vivo glucose imaging in multiple model organisms with an engineered single-wavelength sensor. bioRxiv 571422; doi: https://doi.org/10.1101/571422.
3. Díaz-García CM, Lahmann C, Martínez-François JR, Li B, Koveal D, Nathwani N, Rahman M, Keller JP, Marvin JS, Looger LL, Yellen G. Quantitative in vivo imaging of neuronal glucose concentrations with a genetically encoded fluorescence lifetime sensor. J Neurosci Res. 2019 Aug;97(8):946-960. doi: 10.1002/jnr.24433. Epub 2019 May 20. PMID: 31106909; PMCID: PMC6565483.

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