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Mapping and modulating integrin mediated interactions

Project description

Novel therapeutics for malfunctioning cellular 'sticky stuff' could be around the corner

Integrins are a superfamily of cell adhesion molecules that promote stable interactions between cells and the extracellular matrix. They are receptors that weakly bind extracellular matrix proteins, sort of like Velcro. However, their function is much more than mechanical – they are bidirectional signalling proteins, and their activities, modulation and roles are quite complex. The same integrin can have different ligand specificities in different cell types, and dysfunction of integrins is linked to numerous diseases. The EU-funded MIMIC project is conducting a comprehensive experimental and computational investigation of integrin signalling that will lead to a platform for the design of integrin inhibitors for therapeutic applications.

Objective

Multicellular life depends on the effective communication between cells and their surroundings. One of the primary conduits for cellular interactions is the membrane-embedded receptor family of integrins. Integrins are crucial for several key biological processes, from blood clotting, to proper immune response. Integrin misregulation is at the heart of several diseases, such as Crohn’s disease, MS, or cancer, and integrins are targeted by several viruses as entry points. Yet, our current drugs are not capable of efficiently combating these diseases, as we do not have sufficient molecular and network level knowledge of how integrins work.

The main research objective of MIMIC is to develop an original hybrid in silico/in vitro framework that allows the identification and characterization of unknown elements of integrin signaling. It will present the first such systematic large-scale effort, integrating computational modeling with state-of-the-art experimental techniques. MIMIC will provide the first structured description of integrin ligand specificity profiles, extending our current limited descriptions of extracellular integrin interactions. Thus, MIMIC will be the missing link between integrin research and recent advancements in linear motif research.

The developed framework will not only enable the identification of currently unknown integrin ligands, but will also lay the foundations for innovative approaches in the development of therapeutic agents for integrin-related diseases. Building on the developed experimentally verified computational models, I will construct a novel peptide-based inhibitor design pipeline. MIMIC will provide a structural basis for currently missing immune-specific interactions in atomic detail. I will use this knowledge to design the first immunomodulatory peptide-based integrin inhibitor, serving as a proof-of-concept for future therapeutic applications.

Coordinator

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Net EU contribution
€ 162 806,40
Address
Meyerhofstrasse 1
69117 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
Links
Total cost
€ 162 806,40