• Project No: NCKIR11
  • Intake: 2022 KIR Non Clinical

Supervisor: Professor Jagdeep Nanchahal

Co-Supervisor 1: Associate Professor Fritzsche

Co-supervisor 2: Associate Professor Tal Arnon

Joint Supervisor(s): Dr Ana Espirito Santo, Dr Thomas Layton

PROJECT OVERVIEW

Chronic respiratory diseases are a leading cause of morbidity and mortality worldwide, affecting over 7% of the global population.1 A treatment that promotes regeneration lung damage would revolutionise the management of patients. Lung has an inherent capacity to regenerate. As in many other tissues, resident stem and progenitor cells in the lung are crucial for homeostasis but can also respond to respond to injury to promote regeneration. Alveolar type 2 (AT2) cells act as resident stem and progenitor cells, giving rise to type 1 alveolar cells when required. In the presence of severe injury, secretory cells in the distal airways can also give rise to new AT2 cells.2

We showed that administration of fully-reduced HMGB1 promotes regeneration of multiple tissues, including bone, skeletal muscle and blood.3 This project will focus on mapping the landscape of lung regeneration and define how HMBG1 regulates stem and progenitor cells during lung 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 lung disease, fate mapping studies and human and mouse lung organoids. Our expertise in computational biology4,5 will support the construction of a single cell atlas of lung repair to identify target cells and processes. These quantitative analysis methods will be critically underpinned by the application of the new lattice light sheet technology available in the recently established Oxford-Zeiss Centre of Excellence.

KEYWORDS

Lung disease, Lung regeneration, stem and 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 and experts in imaging and modelling. 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 lung diseases. There is support available from post-doctoral scientists and lab managers in our groups. In summary, you will be working within:

 

  • Cutting-edge lung biology and next generation sequencing techniques available in-house, including tissue culture, cell sorting, organoids, lung 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 lung 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. Collaborators GBDCRD. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med 2020; 8(6): 585-96.
  2. Choi J, Jang YJ, Dabrowska C, et al. Release of Notch activity coordinated by IL-1beta signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration. Nat Cell Biol2021; 23(9): 953-66.
  3. Lee G, Espirito Santo AI, Zwingenberger S, et al. Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert. Proceedings of the National Academy of Sciences of the United States of America 2018; 115(19): E4463-E72.
  4. Izadi D, Layton TB, Williams L, et al. Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis. Sci Adv 2019; 5(12): eaay0370.
  5. Layton TB, Williams L, McCann F, et al. Cellular census of human fibrosis defines functionally distinct stromal cell types and states. Nat Commun 2020; 11(1): 2768.

THEMES

Translational medicine, lung regeneration, systems biology and genomics 

CONTACT INFORMATION OF ALL SUPERVISORS

Professor Jagdeep Nanchahal

Email: jagdeep.nanchahal@kennedy.ox.ac.uk

Associate Professor Marco Fritzsche

Email: marco.fritzsche@kennedy.ox.ac.uk

Associate Professor Tal Aron

Email: tal.arnon@kennedy.ox.ac.uk