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  • Intake: OxKEN

PROJECT OVERVIEW

Background: Advances in gene sequencing and imaging technologies are transforming how scientists undertake research in rheumatoid arthritis (RA), permitting human data driven therapy development.  Using blood and tissue biopsies, we have been developing gene expression maps in joint pathology.  Although these datasets have provided key insights into disease, they lack temporal and spatial information limiting their impact on therapeutic discovery and development. Thus, the challenge is to develop and apply new technologies that can provide new insights into RA and identify a cure.

 Project Objectives

Using a combination of data analytics, computer simulations and experimental validation to identify disease mechanisms and use artificial intelligence to determine if combinations of existing therapeutics developed to treat cancer or other autoimmune diseases could be a CURE for RA.

Approach: In this project the student will develop and utilise multi-scale computational models, to simulate cellular and molecular interactions in time and space; and apply machine learning-based approaches to identify optimal therapeutic intervention strategies.  In this research program we will utilise primary human RA datasets to build computer models focusing on two key disease mechanisms, joint inflammation and cartilage and bone destruction.  Using the power of high performance computing, millions of computer simulations can be run, and artificial intelligence applied to identify novel intervention strategies.  This will involve screening existing therapeutics that could potentially be repurposed to treat RA.  The outputs from these simulations will be validated using human cell culture and in animal models.  Because all computer models will be designed using primary human datasets, the translation of predictions to human clinical medicine will be de-risked. This novel approach has the potential to significantly change how therapies for rheumatoid arthritis are identified

Specific Project Aims

  1. Develop a multi-scale temporal and spatial model of macrophage – sublining layer fibroblast (Thy1+) function in human synovium, built on single cell RNAseq, cytometry and immunohistochemistry datasets from early and chronic RA permitting simulation of receptor-ligand interactions and signaling processes in the formation, maintenance and potential resolution of the inflammatory pathology.
  2. Generate a computational simulation of lining layer fibroblast (Thy1-PRG4+) migration and invasion of bone and cartilage to identify key regulators of fibroblast directed migration and destructive potential that can be selectively targeted.

Thus the aim of this DPhil project will be to use a combination of modelling, machine learning and experimental validation to identify potential therapeutic targeting strategies for human inflammatory disease.

KEYWORDS

Computational modelling, systems biology,

TRAINING OPPORTUNITIES

The student will be based in the Kennedy Institute of Rheumatology taking advantage of data from world leading technologies in the institute including confocal microscopy, high dimensional Cell Dive imaging and 3D light sheet microscopy. obtain training in key cutting-edge technologies including: 3D light sheet and multi-plex high dimensional imaging; Spatial genomics and big data analysis. They will have access to BMRC computing cluster and appropriate systems biology training and learning computational/mathematical skills including use of Matlab or higher level programming languages.

KEY PUBLICATIONS

  1. Cosgrove J, Novkovic M, Albrecht S, Pikor NB, Zhou Z , Onder L, Mörbe U, Cupovic J, Miller H, Alden K, Thuery A, O’Toole P, Pinter R, Jarrett S, Taylor E, Venetz D, Heller M, Uguccioni M, Legler DF, Lacey CJ, Coatesworth A, Polak WG, Cupedo T, Manoury B, Thelen M, Stein JV, Wolf M, Leake MC, Timmis J, Ludewig B, Coles MC, B-cell Zone Reticular Cell Microenvironments Shape CXCL13 Gradient Formation, Nature Communications, 2020, Jul 22;11(1):3677. doi: 10.1038/s41467-020-17135-2.
  2. Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Lorsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD, Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis, Nature. 2019 Jun;570(7760):246-251. doi: 10.1038/s41586-019-1263-7
  3. Nayar S, Campos J, Smith CG, Iannizzotto V, Gardner DH, Mourcin F, Roulois D, Turner J, Sylvestre M, Asam S, Glaysher B, Bowman SJ, Fearon DT, Filer A, Tarte K, Luther SA, Fisher BA, Buckley CD, Coles MC, Barone F, Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.  Proc Natl Acad Sci U S A. 2019 Jun 18. pii: 201905301. doi: 10.1073/pnas.1905301116.
  4. Brown LV, Gaffney EA, Wagg J, Coles MC. An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination. J R Soc Interface. 2018 Mar;15(140). pii: 20180041. doi: 10.1098/rsif.2018.0041.
  5. Aschenbrenner D, Quaranta M, Banerjee S, Ilott N, Jansen J, Steere B, Chen YH, Ho S, Cox K, Arancibia-Cárcamo CV, Coles M, Gaffney E, Travis SP, Denson L, Kugathasan S, Schmitz J, Powrie F, Sansom SN, Uhlig HH. Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance, Gut. 2020 Oct 9:gutjnl-2020-321731. doi: 10.1136/gutjnl-2020-321731

CONTACT INFORMATION OF ALL SUPERVISORS

Mark Coles

Eamonn Gaffney