K J Patel
Stem cell metabolism and it’s consequences on genetic integrity
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This project will extend on discoveries made by four previous PhD students in my lab (reference 1,2,3 and 4). We have found that mammalian blood stem cells generate certain highly toxic metabolites that can cause irreversible damage to the DNA of these vital cells. These toxic metabolites are simple reactive aldehydes, and the blood stem cells first clears them using a battery of enzymes (Aldehyde dehydrogenases), but if they accumulate and damage DNA then this is reversed by a specific DNA repair pathway (Fanconi anaemia repair pathway). Perturbation of this protective mechanism leads to rapid loss of blood production and cancer predisposition in humans and mice.
The projects will aim to identify the origin of these metabolites, how they damage the DNA of stem cells and what are the consequences when this damage persists. The experimental approach will be to use somatic cell genetics using state of the art genome editing technology (CRISPR –CAS), haploid embryonic stem cell lines, and genetically engineered mice. Stem cell cultures will be established and through using cells obtained from special reporter mice, liver and bowel organoid cultures will also be established. Such in vitro stem cell culture systems in combination to stem cells within transgenic mice will be studied further to define how such reactive metabolites arise, how they damage DNA in these situations, and what might be the functional consequences of this.
Oberbeck, N., Langevin, F., King, G., Wind, N., Crossan, G.P. and Patel, K.J. (2014)
Maternal aldehyde elimination during pregnancy preserves the fetal genome.
Molecular Cell 55:807–817.
Garaycoechea, J.I., Crossan, G.P., Langevin, F., Daly, M., Arends, M.J. and Patel, K.J. (2012)
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
Langevin, F., Crossan, G.P., Rosado, I.V., Arends, M.J. and Patel, K.J. (2011)
The Fanconi Anaemia DNA repair pathway counteracts the toxic effects of naturally produced aldehydes.
Crossan, G.P. et al (2011)
Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia.
Nature Genetics, 43:147-52.