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Deciphering acetaldehyde biochemistry using small molecule tools: from hangovers to cancer (GTA 20 HOP)


Project Description

Acetaldehyde, the first product of ethanol metabolism, is a human toxin and carcinogen. Many of the intoxicating and disease-inducing effects of drinking alcohol, as well as the symptoms of hangovers, are likely due to acetaldehyde. How acetaldehyde induces these effects is, however, unclear. Like similar biological aldehydes such as formaldehyde and methylglyoxal, acetaldehyde is highly reactive with biomolecules, forming quasi-stable adducts – it is likely these adducts are responsible for acetaldehyde’s biology, although mechanistic insight is lacking.

Defining how acetaldehyde affects cellular functions has the potential to revolutionise treatments for alcoholism and alcohol-related diseases. A major hindrance to such studies, however, has been a lack of chemical tools and methods to detect and modulate cellular acetaldehyde concentrations. This project will therefore develop a novel ‘acetaldehyde chemical toolkit’ of small molecule acetaldehyde delivery agents and scavengers to enable controllable manipulation of cellular acetaldehyde levels for the first time. These tools will then be used in cellular experiments to determine the mechanisms underpinning acetaldehyde’s biological effects.

Overall, this chemically-focused but interdisciplinary project will give the first systematic appraisal of acetaldehyde’s biochemistry in human cells, and will almost certainly lead to novel therapies for numerous diseases.

Methodology

Acetaldehyde delivering agents and scavengers will be inspired by analogous formaldehyde tool molecules already developed in our lab. Acetaldehyde delivery/scavenging will be controlled by incorporating pro-drug strategies, including esterase-sensitive groups and/or photo-caging. All compounds will be synthesised from simple precursors and will be tested for their acetaldehyde releasing/sequestering propensities before use.

Initial cellular experiments will profile the toxiciy of the acetaldehyde delivery and scavenging compounds across a number of human cell types. The reactions of the tool compounds will then be analysed in human cell lysates (and later in live cells) using NMR and mass spectrometry. These experiments will involve quantifying cellular acetaldehyde concentrations upon treatment with tool compounds using novel scavenging methodologies. Finally, the biological effects of the tool compounds will be determined in phenotypic assays on human cells.

Academic entry requirements

UK Bachelor Degree with at least 2:1 in a relevant subject or overseas equivalent.

University of Leicester English language requirements apply (where applicable).

UK/EU applicants only.

Application Instructions

When applying, please ensure we have received all of the following required documents by Tuesday 4th February 2020:

- Application Form
- 2 academic references
- CV
- Undergraduate transcripts

If you have completed your undergraduate degree, we will also require your undergraduate degree certificate.

If you have completed a postgraduate degree, we will also require your transcripts and degree certificate.

If we do not have the required documents by the closing date, your application may not be considered for the studentship.

Please refer to guidance at - https://le.ac.uk/study/research-degrees/funded-opportunities/chem-gta-2020

Funding Notes

Fully funded 4 years.

UK/EU tuition fee waiver.

Stipend at UKRI rates.

References

1. Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells, J. I. Garaycoechea, G. P. Crossan, F. Langevin, L. Mulderrig, S. Louzada, F. Yang, G. Guilbaud, N. Park, S. Roerink, S. Nik-Zainal, M. Stratton, K. J. Patel*, Nature, 2018, 553, 171–177.

2. The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies, E. Quertemont, S. Tambour, E. Tirelli, Progress in Neurobiology, 2005, 75(4), 247–274.

3. Studies on the reaction of glutathione and formaldehyde using NMR, R. J. Hopkinson, P. S. Barlow, C. J. Schofield*, T. D. W. Claridge*, Organic and Biomolecular Chemistry, 2010, 8, 4915-4920.

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