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Kennedy Trust Prize Studentships

  • Project No: KTPS-Clinical-3
  • Intake: 2021 KTPS

PROJECT Outline

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver in the Western world, affecting 30% of the adult population in the USA and encompasses non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). NAFL and NASH each carry a significant morbidity and mortality with 2-3% and 15-20% respectively progressing to cirrhosis, with some developing hepatocellular carcinoma. Indeed, NAFLD will soon represent the principal indication for liver transplantation in the USA, with the attendant problems of immunosuppression and shortages of suitable donors. Despite the huge disease burden, there is no approved therapy for patients with NASH. Immense effort is concentrated in developing potential pharmacological treatments and several agents are being evaluated in early phase clinical trials. Even once effective therapeutics have been developed, the focus will remain on preventing further damage and relying on the regenerative capacity of the liver aided by improvements in dietary habits, bariatric surgery and exercise.

A treatment that promotes regeneration hepatocellular damage would revolutionise the management of patients. Liver has an inherent capacity to regenerate and we have previously identified a pool of resident progenitor cells in the liver that together with hepatocytes contribute to liver regeneration (Raven et al., 2017). These progenitor cells act as the facultative source of regeneration when hepatocyte regeneration fails. HMGB1 is released from damaged hepatocytes during liver injury, in particular, in the setting of cellular senescence. The release of HMGB1 from senescing hepatocytes may act on liver resident progenitor cells and alter cell fate decision and exogenous administration of HMGB1 is an attractive option for promoting endogenous regeneration during chronic liver disease. We showed that administration of fully-reduced HMGB1 promotes regeneration of multiple tissues, including bone, skeletal muscle and blood (Lee et al., 2018), and other have shown that it promotes hepatocyte proliferation following liver injury (Tirone et al., 2018).

This project will focus on mapping the landscape of liver regeneration and define how HMBG1 regulates progenitor cells during chronic hepatic injury. It will be powered by the integration of advanced next generation sequencing techniques, such as single cell RNA-seq and ChIP-seq, with established murine models of liver disease, fate mapping studies and liver organoids. Our expertise in computational biology (Croft et al., 2019; Layton et al., 2020) will support the construction of a single cell atlas of liver repair and prioritise potential disease areas and biomarkers.

KEYWORDS

Chronic liver disease, liver regeneration, progenitor cells, organoids, single cell RNA-sequencing

TRAINING OPPORTUNITIES

The successful candidate will benefit from supervision by a surgeon scientist with a focus on translational medicine, a clinician scientist with expertise in computational biology and translational research, as well as two renowned authorities on liver diseases, including a senior hepatologist. In addition, you will be supported by two junior supervisors with expertise in HMGB1 biology and computational biology.

You will be based in the modern building and laboratories of the Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation. The project will use a combination of human samples, organoids and murine models of chronic liver diseases. There is support available from post-doctoral scientists and lab managers in our groups. In summary, you will be working within:

  • Cutting-edge liver biology and next generation sequencing techniques available in-house, including tissue culture, cell sorting, organoids, chronic liver diseases models and single cell RNA-sequencing analysis
  • Emphasis on translational work: findings from human and murine samples in conjunction with next generation sequencing to promote liver regeneration can have a high impact on future therapeutic development
  • Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists 
  • Highly collaborative environment with expertise ranging from molecular and cell biology to in vivo models and computational biology / genomics analysis. You will also have the opportunity to participate in several other collaboration within the University of Oxford and worldwide.

KEY PUBLICATIONS 

  1. Croft, A.P., J. Campos, K. Jansen, J.D. Turner, J. Marshall, M. Attar, L. Savary, C. Wehmeyer, A.J. Naylor, S. Kemble, J. Begum, K. Durholz, H. Perlman, F. Barone, H.M. McGettrick, D.T. Fearon, K. Wei, S. Raychaudhuri, I. Korsunsky, M.B. Brenner, M. Coles, S.N. Sansom, A. Filer, and C.D. Buckley. 2019. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570:246-251. doi: 10.1038/s41586-019-1263-7.
  2. Layton, T.B., L. Williams, F. McCann, M. Zhang, M. Fritzsche, H. Colin-York, M. Cabrita, M.T.H. Ng, M. Feldmann, S.N. Sansom, D. Furniss, W. Xie, and J. Nanchahal. 2020. Cellular census of human fibrosis defines functionally distinct stromal cell types and states. Nat Commun 11:2768. doi: 10.1038/s41467-020-16264-y.
  3. Lee, G., A.I. Espirito Santo, S. Zwingenberger, L. Cai, T. Vogl, M. Feldmann, N.J. Horwood, J.K. Chan, and J. Nanchahal. 2018. Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert. Proc Natl Acad Sci U S A 115:E4463-E4472. doi: 10.1073/pnas.1802893115.
  4. Raven, A., W.Y. Lu, T.Y. Man, S. Ferreira-Gonzalez, E. O'Duibhir, B.J. Dwyer, J.P. Thomson, R.R. Meehan, R. Bogorad, V. Koteliansky, Y. Kotelevtsev, C. Ffrench-Constant, L. Boulter, and S.J. Forbes. 2017. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547:350-354. doi: 10.1038/nature23015.
  5. Tirone, M., N.L. Tran, C. Ceriotti, A. Gorzanelli, M. Canepari, R. Bottinelli, A. Raucci, S. Di Maggio, C. Santiago, M. Mellado, M. Saclier, S. Francois, G. Careccia, M. He, F. De Marchis, V. Conti, S. Ben Larbi, S. Cuvellier, M. Casalgrandi, A. Preti, B. Chazaud, Y. Al-Abed, G. Messina, G. Sitia, S. Brunelli, M.E. Bianchi, and E. Venereau. 2018. High mobility group box 1 orchestrates tissue regeneration via CXCR4. J Exp Med 215:303-318. doi: 10.1084/jem.20160217.

THEMES

Translational medicine, liver regeneration, systems biology and genomics 

CONTACT INFORMATION OF ALL SUPERVISORS:

Professor Jagdeep Nanchahal

Professor Chris Buckley

Dr Wei-Yu-Lu

Professor Philip Newsome

Dr Ana Espirito Santo

Dr Thomas Layton

 

 

 

 

 

 

 

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