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Biochemical pathology of diabetes: Mechanisms of cysteine depletion during hyperglycaemia (HAMILTONC_U22SF)


   School of Pharmacy

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  Dr C Hamilton  No more applications being accepted  Self-Funded PhD Students Only

About the Project

In humans, the cysteine-containing tripeptide glutathione (GSH) is an essential thiol cofactor that maintains an intracellular reducing environment to protect against oxidative stress, which causes lipid, protein & DNA damage.

Glutathione biosynthesis is limited by the availability of cysteine. In diabetics, hyperglycaemia causes long-term health complications, because elevated levels of glycolytic intermediates (dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP)) causing oxidative stress, which depletes intracellular glutathione and cysteine. This reduces the rate of glutathione biosynthesis, which explains why the glutathione levels are lower. However, nobody has ever established how and why the cysteine levels are reduced. We have recently discovered that cysteine can be chemically trapped by reaction with DHAP and GAP to form thiohemiacetals.

This project will characterise these reactions in detail (both in solution and in cells). Proving and understanding these biochemical reactions in vivo will fill a substantial gap in our knowledge of cellular biochemistry in diabetics. It will underpin future development of cysteine rich diets as a way to lower the long term health complications caused by hyperglycaemia in diabetics  It will also establish the existence of an alternative intracellular reservoir for cysteine which could be of relevance across all living organisms.

The project offers extensive interdisciplinary training and research experience in analytical biochemistry, enzymology, whole cell NMR spectroscopy and cell biology. This will involve working within different research groups within the School of Pharmacy and The School of Biology.

The project is suited for a student with a degree in Chemistry, Pharmaceutical or Biological Sciences or a related discipline.

An earlier start date of 1 February or 1 June 2022 may be possible, but this should be discussed with the primary supervisor in the first instance


Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at https://www.uea.ac.uk/about/university-information/finance-and-procurement/finance-information-for-students/tuition-fees
A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. Applicants should contact the primary supervisor for further information about the fee associated with the project.

References

1. Lushchak VI. Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions. Journal of Amino Acids. 2012;2012:26.
2. Araki E, Nishikawa T. Oxidative stress: A cause and therapeutic target of diabetic complications. Journal of Diabetes Investigation. 2010;1(3):90-6.
3. Sekhar RV, McKay SV, Patel SG, Guthikonda AP, Reddy VT, Balasubramanyam A, et al. Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine. Diabetes Care. 2011;34(1):162-7.
4. Jin X, Kang S, Tanaka S, Park S. Monitoring the Glutathione Redox Reaction in Living Human Cells by Combining Metabolic Labeling with Heteronuclear NMR. Angewandte Chemie International Edition. 2016;55(28):7939-42.
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