Novel regulation of inflammatory signalling by the ciliome
The primary cilium is an organelle that was largely ignored for over a hundred years but is now established to be a nexus for organising cell signalling . A collection of human congenital pathologies are due to dysfunction of the cilium's associated protein machinery, the ciliome, and the role of these proteins in disease is an exciting new frontier. We discovered that ciliary trafficking proteins are both altered by and critical to the cell response to inflammatory cytokines, including at the level of the NFκB cascade . The project will investigate this further. The plethora of responses to cytokines, and the signalling cascades that underpin these, are important to the differentiation, physiology and pathological behaviour of most cell types. If the ciliome is able to exert tuning influence to this signalling, this represents an opportunity for exploiting the connection between aberrant signalling and pathogenesis. The project will investigate the hypothesis that the ciliome is a spatial-temporal bottleneck for the regulation of inflammatory signalling with the following aims:
- To dissect the molecular identity, nature and scope of the interaction between the ciliome and cytokine signalling.
- To visualise the interplay between the nanoscale ciliary architecture and cytokine-induced signalling cascades.
- To investigate the importance of the ciliome in the tissue response to inflammatory pathogenesis.
- To identify changes to the ciliome in inflammatory disease.
To meet these objectives a combination of molecular biology and microscopy will be used and the findings translated to the disease context. Microscopy will include live capturing of dynamic signalling  using confocal and total internal reflection fluorescence microscopy (TIRF), and super-resolution techniques such as SIM, STED and STORM. Clinical samples and disease models will be investigated to translate the findings. The student will investigate the cilium in tissue and cell samples by means of immunofluorescence imaging at the Kennedy institute but also 3View electron microscopy and tomography at the Sir William Dunn school of Pathology. The student will also collaborate with Professor Vincent and within the ARUK centre for OA pathogenesis, with other groups at the Kennedy including those focussed on inflammatory disease such as R.A (Williams) and with wider domestic and international collaborations the Wann group has fostered. Professor Dustin will serve as a co-advisor and contributes experience with TIRFM, a tool his lab uses to study the immunological synapse, another nexus of signalling events.
The Kennedy institute is a world-renowned research centre in a brand new state-of-the- art facility. In addition to full laboratory training a core curriculum of 20 lectures will be taken in the first term to provide a solid foundation in musculoskeletal sciences immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.
- Nachury, M.V., How do cilia organize signalling cascades? Philos Trans R Soc Lond B Biol Sci, 2014. 369(1650).
- Wann, A.K., J.P. Chapple, and M.M. Knight, The primary cilium influences interleukin-1beta-induced NFkappaB signalling by regulating IKK activity. Cell Signal, 2014. 26(8): p. 1735-42.
- Craft, J.M., J.A. Harris, S. Hyman, P. Kner, and K.F. Lechtreck, Tubulin transport by IFT is upregulated during ciliary growth by a cilium-autonomous mechanism. J Cell Biol, 2015. 208(2): p. 223-37.
Molecular, cell and systems biology; Musculoskeletal science