Kennedy Trust Prize Studentships
Investigating the structural basis of innate immunity in health and disease
Pattern recognition underpins innate immunity. Pathogenic molecules (pathogen associated molecular patterns; PAMPs) and endogenous molecules specifically expressed upon tissue damage (damage associated molecular patterns; DAMPs) are detected by pattern recognition receptors (PRRs), triggering the activation of inflammatory signalling pathways that fight infection and mediate tissue repair. Detailed insights into how PRRs sense pathogen invasion by recognizing PAMPs from bacteria, fungi, protozoa and viruses have demonstrated how a specific immune response to distinct microbial threat is mediated, and enabled rational drug design to combat infectious disease.
However, there is almost no description of how DAMPs are recognized as inflammatory triggers. DAMPs are essential to activate inflammation and repair upon sterile tissue damage, but they are also major drivers of dysregulated inflammation associated with autoimmune, fibrotic and metabolic diseases, and tumors. Emerging evidence indicates that these stimuli activate PRRs very differently to pathogenic stimuli, creating the opportunity to design drugs that specifically target pathological sterile inflammation, leaving intact host defence again infection.
This project will dissect the structural basis of DAMP-mediated PRR activation; we aim to generate the first crystal structure of an endogenous inflammatory trigger complexed to its receptor, we will explore whether a molecular code we identified as a pro-inflammatory tag, earmarking proteins for recognition by PRRs, is common to all endogenous inflammatory stimuli or exists uniquely in specific subsets, and we will determine whether deleting this tag enables molecules to remain below the radar of innate immune surveillance. Finally, using high resolution, single molecule microscopy we will analyse whether PAMP- and DAMP-receptor complexes exhibit different intracellular trafficking, resulting in the activation of distinct inflammatory signalling pathways.
The Kennedy Institute is a world-renowned research centre, located in a brand new facility, housing basic and clinician scientists working on diverse aspects of immunology and inflammation. This project will combine state of the art structure/function analysis with cellular immunology; full training will be provided in a range of immunological, biophysical and molecular biology techniques. Students will also have the opportunity to work closely with the crystallography team at the SGC and the nearby Diamond Light Source. The PhD programme includes a core curriculum of 20 lectures in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly group meetings, and will be expected to attend seminars in the department and relevant seminars in the wider University. Students will attend national and international meetings, at which they will present their data.
- Bryant, C.E. et al. Crit Rev Biochem Mol Biol 50, 359-79 (2015).
- Midwood, K.S., et al. Nature Medicine. 15 (7):774-80 (2009).
- Piccinini, A.M., et al., Science Signalling. 9 :ra86 (2016).
Immunology; Cancer; Translational Medicine.
Prof. Kim Midwood, Kennedy Institute, University of Oxford