Is glutamine the answer to reversing blood stem cell ageing

As our ageing population grows it is becoming increasingly important to better understand the changes that occur during physiological ageing. Ageing drives intrinsic metabolic changes that alter normal physiology and result in tissue dysfunction and the development of numerous age-related diseases. This project will aim to better understand the age-related metabolic changes that occur in blood stem cells with a focus on glutamine metabolism and the impact this has on blood production. Whilst our previous work has demonstrated that the environment in which blood stem cells reside contributes to the impaired response to infection other preliminary has shown that blood stem cells also acquire intrinsic changes that may alter their metabolic function. Therefore, this project aims to study the intrinsic metabolic changes of blood stem cells and how this impacts metabolic output. The PhD student will be trained in vivo techniques including animal handling, isolation of primary cells and techniques to assess metabolic and functional characteristics of cells including FACS analysis, liquid chromatography/mass spectrometry to track metabolites, qPCR to analyse nucleic acids and western blot, ELISA and metabolic assays. This will give them a number of valuable transferrable skills which will help their scientific career progression. The project will be carried out at the Rushworth Lab based at Norwich Medical School, UEA, which combines research laboratories with medical training facilities.

References

p16INK4A-dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors. Hellmich C, Wojtowicz E, Moore JA, Mistry JJ, Jibril A, Johnson BB, Smith JGW, Beraza N, Bowles KM, Rushworth SA.
Blood Adv. 2023 Jan 24

Plasma cell-derived mtDAMPs activate the macrophage STING pathway, promoting myeloma progression. Jibril A, Hellmich C, Wojtowicz EE, Hampton K, Maynard R, De Silva R, Fowler-Shorten DJ, Mistry JJ, Moore JA, Bowles KM, Rushworth SA.Blood. 2023 Jun 22

Haematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion. Wojtowicz EE, Mistry JJ, Uzun V, Hellmich C, Scoones A, Chin DW, Kettyle LM, Grasso F, Lord AM, Wright DJ, Etherington GJ, Woll PS, Belderbos ME, Bowles KM, Nerlov C, Haerty W, Bystrykh LV, Jacobsen SEW, Rushworth SA, Macaulay IC. Genome Biol. 2023 June

Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection. Mistry JJ, Hellmich C, Moore JA, Jibril A, Macaulay I, Moreno-Gonzalez M, Di Palma F, Beraza N, Bowles KM, Rushworth SA. Nat Commun. 2021 Dec

ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Mistry JJ, Marlein CR, Moore JA, Hellmich C, Wojtowicz EE, Smith JGW, Macaulay I, Sun Y, Morfakis A, Patterson A, Horton RH, Divekar D, Morris CJ, Haestier A, Di Palma F, Beraza N, Bowles KM, Rushworth SA. Proc Natl Acad Sci U S A. 2019 Dec 3