Pericellular mechanisms of fibrillin microfibril assembly.

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Fibrillin microfibrils are filamentous structures laid down by cells as part of the 'extracellular matrix (ECM)'. They form bundles of microfibrils that interact with cells and also form the framework for the formation of 'elastic fibres', which endow the essential property of elastic recoil on dynamic tissues such as blood vessels, lungs, skin and ligaments. The importance of fibrillin is clearly highlighted by the many serious diseases that are caused by genetic defects in fibrillin (e.g. Marfan syndrome, which is associated with life-threatening cardiovascular defects), and by the degeneration of microfibrils in ageing and diseases of blood vessels, lungs (emphysema), loss of skin elasticity, and certain eye defects. Despite their essential nature, it is still not understood how microfibrils form, which has severely limited treatment advances. This proposal is to build on exciting new discoveries from my group which give important new insights into their assembly and function. The study will provide new insights into how mutations in fibrillin-1 cause severe heritable diseases, and form the basis for improved strategies to restore microfibrils to tissues with compromised elasticity. The project is of great importance to regenerative medicine, which is an MRC priority because there is a major unmet clinical need to develop new treatments to restore function to compromised elastic tissues and organs. My group is ideally placed to conduct this specialised research because we are internationally-renowned for our expertise and discoveries in fibrillin/elastic fibre biology, and we will build on our have recent discovery of cell type-specific mechanisms that throw new light on this complex process. Thus it is very timely and directly addresses the MRC Priority 'Resilience, Repair and Replacement'.