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Uncovering the role of the iRhom2-ADAM17 interaction in inflammatory signalling

Project description

Identification of novel targets for modulating inflammatory signalling

Manipulation of the inflammatory process is a desirable treatment strategy with application in many diseases. Scientists of the EU-funded iRhomADAM project propose to target the metalloprotease ADAM17 known to cleave and release the key inflammatory cytokine TNFalpha. The project will focus on the interaction of ADAM17 with iRhom2, a protein identified to regulate trafficking, maturation and stability of ADAM17. Structural insight into the interaction between these two proteins will help design inhibitors and test them in macrophages. Collectively, the iRhomADAM project has the potential to identify novel targets of inflammatory signalling.

Objective

The primary inflammatory cytokine, TNFalpha, is a transmembrane protein that requires cleavage by the metalloprotease ADAM17 for its release. Aberrant release of TNFalpha is a hallmark of cancer, chronic inflammation and autoimmune syndromes. The rising prevalence of these widespread diseases necessitates new approaches to manipulate inflammatory signalling, which is the overarching goal of this proposal. Recent studies demonstrate that iRhoms regulate trafficking, maturation and stability of ADAM17. Without iRhoms, TNFalpha shedding is abolished. The aim of this research is to dissect the transmembrane interaction between iRhom2 and ADAM17, which will support the required information to design the first iRhom inhibitor. Using FRET spectroscopy and ADAM17 activity assays, I will first search for essential residues at the transmembrane interface between iRhom2 and ADAM17. Next, I will use rationally designed helical peptides to competitively inhibit the transmembrane interaction. Last, I will test the effect of any inhibitors I develop in an in-vivo human macrophage model and use it to study the significance of this interaction. This study will provide an important mechanistic understanding of iRhom biology, with an emphasis on their mode of specific transmembrane recognition. Moreover, by developing the first specific iRhom2-ADAM17 complex inhibitor, I will establish iRhom2 and ADAM17 as therapeutically relevant targets to manipulate inflammation.

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Net EU contribution
€ 212 933,76
Address
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
United Kingdom

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Region
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 212 933,76