Assembly of fibrillin microfibrils and elastic fibres

Elastic fibres are large structural elements of dynamic tissues such as blood vessels, lungs skin and ligaments. They comprise a core of the protein elastin surrounded by microfibrils that are based on the protein fibrillin. They are assembled by cells and deposited in their surrounding ?extracellular matrix?. These fibres endow tissues with the essential property of elasticity that, for example, allows blood vessels to expand and recoil with pulsatile blood flow. Defects in elastic fibres accumulate in ageing leading to aortic aneurysms (degenerative blood vessel walls) and lung emphysema (defective breathing) which have life-threatening consequences, whilst chronologically or sun aged skin loses elasticity and accumulates wrinkles. There are also a number of serious inherited elastic fibre diseases that are caused by mutations in elastic fibre components; they include Marfan syndrome (caused by mutations in the microfibril protein fibrillin-1), supravalvular stenosis (caused by elastin mutations), and cutis laxa (caused by mutations in elastin or other elastic fibre proteins). In this study, we will determine how elastic fibres assemble by testing the hypothesis that the cell surface orchestrates the molecular interactions needed to assemble elastic fibres. This research will provide important new insights that will contribute to advancing therapeutic approaches to restore elastic fibre function in ageing and disease.

Elastic fibres of the extracellular matrix endow dynamic tissues such as blood vessels, lungs, skin and ligaments with the essential properties of resilience and elastic recoil. Their critical importance to life is emphasised by elastic fibre defects that cause common life-threatening diseases such as aortic aneurysms and emphysema, and several severe heritable disorders such as Marfan syndrome and cutis laxa. Elastic fibres comprise a crosslinked elastin core and an outer mantle of fibrillin microfibrils. Our research has highlighted the essential contribution of the cell-matrix interface to microfibril formation, and sets the scene now to deliver a step-change in understanding the hierarchical process of elastic fibre assembly. The hypothesis to be tested is that the cell?matrix interface orchestrates the cell surface assembly of microfibrils, the formation of elastin microassemblies, and their convergence to form elastic fibres. This timely study will provide new insights that will advance therapeutic strategies to restore elastic fibre function, and inform genotype-phenotype relationships in heritable disorders.