Wann Group | Primary Cilia in Inflammatory Signalling
Cells use unique spaces to organise the messaging that modifies their behaviour and respond to their environment. Our research looks at how one such space - the primary cilium - affects the way cells respond to inflammation.
Cells use unique spaces and machinery to organise the messaging that modifies their behaviour and their responses to their environment. Our research looks at how one such space, the primary cilium, and its associated machinery, coined the ciliome, affects the way cells behave in disease. Particularly we are interested in the context of pathological signalling downstream to 'inflammatory' stimuli.
The primary cilium is a singular organelle within cells. The cilium is about 1/5000th of a mm in width and has specialised trafficking. Despite being largely ignored for over a century we now know faulty ciliary function is behind a collection of human diseases. This research group investigates the wider context to the finding that ciliary trafficking regulates how some cells respond to inflammatory stimuli. We aim to understand how this happens; whether this is important in diseases and whether we can exploit cilia regulation of cell biology.
The primary cilium is a nanoscale cellular compartment assembled by the vast majority of cell types upon exit from the cell cycle. This compartment is as little as 1/10,000th of the total cell volume. Each cell usually elaborates a single primary cilium from the template of the mature centriole modified to become the basal body. The cilium therefore has an axonemal skeleton of 9+0 tubulin dimers. We now know cilia are associated with a collection of proteins including axonemal kinesin and dynein motors, intraflagellar transport proteins or IFTs and a collection of supporting proteins. In different cells different proteins are recruited to or accumulate in the cilium. These cilia-associated proteins have been coined the ciliome.
Although first discovered in the late 19th century, the cilium was largely ignored until an explosion of interest around the turn into the 21st century, when it was discovered that a number of human disorders, the ciliopathies, stem from mutations and dysfunction of proteins associated with the cilium or its activity. Cilia and the ciliome are now the subject of research investigating their roles in many cell and tissue types. Potentially ciliary dysfunction may be involved in the genesis and development of diseases beyond the ciliopathies. It is now established to regulate many signalling pathways and therefore is a nexus for tuning much cell biology.
One focus is a novel role for the primary cilium in transducing the response of cells to 'inflammatory' stimuli such as cytokines. Previous work has illuminated a relationship between the cytosolic signalling activated downstream to cytokines, ciliary architecture and the proteins that orchestrate ciliary trafficking. Primary cilia architecture and trafficking are altered by cytokines and the response of cells to cytokines is modified when ciliary trafficking is interfered with. This led to the hypothesis that the primary cilium plays a key role in the regulation of the cell response to cytokines and may be a potential point of exploitable regulation over pathogenic signalling. We now know that the ciliome fine tunes NFκκB signal dynamics and in doing so encodes signal complexity and context-dependent regulation.
The work seeks to establish the mechanism for ciliary influence over such signalling with a view to understanding this role in disease and/or exploiting this to modulate cell behaviour in a variety of contexts. Another related focus is studying the cilium in the neurons that innervate limbs investigating how cytokines change their sensitivity in the context of pain and non-canonical roles for ciliary proteins.
We are also investigating a novel link between the ciliome and the regulation of matrix homeostasis through influence over endocytosis dynamics. This work is identifying a putative axis between the cilium and matrix remodelling through receptor mediated endocytosis that is similarly disturbed in both disease and when ciliary proteins are perturbed. This is the focus of an Arthritis Research UK studentship.
The major current translational focus of this is towards osteoarthritis, a disease with an established inflammatory signalling component. Using a range of techniques from molecular biology through high and super-resolution microscopy through to pathogenesis models we aim also to fundamentally understand ciliary function in the context of the organisation of the cellular and tissue level response to pathological challenge. We are developing pre-clinical models to investigate the role of the ciliome in adult physiology, ageing and disease.
- What is the post-natal and disease-relevant influence of the ciliome?
- What is the molecular nature of the interaction between the ciliome and inflammatory signalling?
- Are the cilium and associated proteins (ciliome) altered in diseases where inflammatory signalling is aberrant?
- What is the role of the cilium in adult tissues of the joint and in osteoarthritis?
- Can we exploit ciliary regulation of signalling?
- How does ciliary traffic modulate broader cell signalling and biology?
Professor Martin Knight and Dr Clare Thompson (Institute of bioengineering, QMUL)
Professor Phillip Beales and Dr Dagan Jenkins and Dr Hannah Mitchison, (Institute of Child Health (cilia disorders group), UCL )
Dr Susan McGlashan (Auckland)
Professor Michael-Titus and Dr Gregory Michael (QMUL)
Professor Paul Chapple (William Harvey research institute, QMUL)
Dr Hiroaki Ishikawa (UCSF)
Professor Jagesh Shah (Harvard)