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EXTRacEllular matrix MEchanochemistry: a solid-state NMR approach

Project description

The extracellular matrix as a platform for studying tissue mechanical history

The extracellular matrix (ECM) is a complex 3D material that forms a scaffold around cells and determines the mechanical properties of structural tissues like bone, tendon and skin. Recent studies demonstrated that covalent bond breaks in the ECM proteins result in chemical modifications that communicate the mechanical history, embedding specific molecular cues into the ECM structure. The EU-funded EXTREME project aims to elucidate the specifics of the ECM mechanochemical modifications as well as how cells recognise them and how they change in ageing and disease. The project will employ the solid-state nuclear magnetic resonance methodology to determine these modifications in the ECM of intact tissues under mechanical deformations.

Objective

The mechanical properties of structural animal tissues like bone, tendon and skin are determined by the extracellular matrix (ECM) of the tissue, a complex, changeable 3D material that forms a scaffold around the tissue’s cells. The matrix is under constant mechanical stress from our everyday movements. When it is damaged, cells in the tissue repair it; where there is repeated damage, cells must strengthen the matrix, not just repair. Thus, drivers of cell behaviour are encoded into the detailed molecular structure of the ECM. For cells to respond appropriately when they re-structure the ECM – simple repair or strengthen, for example – they need access to its mechanical history. However, there is currently little understanding of how the mechanical history of the ECM is encoded into its molecular structure.

New work shows that chemistry happens in the ECM under mechanical strains. Covalent bonds break resulting in chemical modifications to extracellular proteins, the modifications depending on the strain. This suggests Nature has evolved an exquisite mechanism to communicate the mechanical history of the ECM to cells, using mechanochemistry resulting from the forces on the tissues to accumulate specific molecular cues into the ECM.

The challenge now is to determine what these ECM mechanochemical modifications are, how cells use them and how they change in ageing and diseases such as diabetes and cancer. There are few methods to probe atomic structures in highly heterogeneous materials such as the ECM. I have developed solid-state NMR (SSNMR) methodology over the last 15 years to determine molecular structure changes and follow chemistry in the ECM. Here, I will develop an SSNMR approach to determine the chemical modifications to the ECM of intact tissues under mechanical deformations. I will use the new methodology to develop important new insight into how cells interpret their environment that will impact on how we understand human diseases and ageing.

Host institution

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Net EU contribution
€ 3 498 825,00
Address
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 3 498 825,00

Beneficiaries (1)