The function of pattern recognition receptors in immune homeostasis and inflammation

Supervisor:  Prof Alison Simmons

NOD2 is essential for immune defense against intracellular pathogens and has been associated, when expressed in a defective form, with development of Crohns’ disease. We have previously defined functions for NOD2 in induction of autophagy, bacterial destruction and antigen presentation in response to commensal bacteria in a pathway that is dysregulated in Crohn’s. In addition we have defined a novel immunoregulatory function for NOD2, lost in Crohn’s patients cells, involving microRNA-29 mediated limitation of IL-23 release following bacterial recognition. To understand how NOD2 exerts these immune defense functions and define novel drug targets in Crohn’s we have used various large scale molecular approaches to map signaling from NOD2 and other pattern recognition receptors in myeloid cells. This has revealed multiple new hypotheses for pattern recognition receptor function in maintaining immune homeostasis, protection against pathogens or in inflammation and cancer. This DPhil project will involve exploring how  selected pathways operate in the intestinal mucosa in health or disease.  The work will involve gaining experience in cell and molecular biology, confocal and STED microscopy, single-cell technologies such as single-cell RNA sequencing and CyTOF and will involve work using human intestinal cell and tissues and relevant murine models.

The lab is multidisciplinary consisting of a mix of scientists, clinicians, bioinformaticians, and a clinical trials team undertaking support studies in experimental medicine with research endoscopy component. Our work is supported with strong collaborations across the campus and in industry giving an opportunity to directly translate relevant findings. 

References:

  1. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010). NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Medicine Jan;16(1):90-7.  PMID:  19966812.
  2. Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu A M, Morton V, Sun M Y, Jewell D, Coccia M, Harrison O, Maloy K, Schönefeldt S, Bornschein S, Liston A, Simmons A. (2013).  The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity Sep 19;39(3):521-36.  PMID:  24054330.

For further information please contact:

Prof Alison Simmons

Alison.simmons@ndm.ox.ac.uk