Mapping and modulating integrin mediated interactions

Description du projet

De nouvelles thérapies contre les dysfonctionnements de la «substance adhérente» cellulaire pourraient être à portée de main

Les intégrines sont une superfamille de molécules d’adhésion cellulaire qui favorisent les interactions stables entre les cellules et la matrice extracellulaire. Ce sont des récepteurs qui se lient faiblement aux protéines de la matrice extracellulaire, un peu comme du velcro. Cependant, leur fonction va bien au-delà de la simple mécanique: il s’agit de protéines de signalisation bidirectionnelle, et leurs activités, modulations et rôles restent assez complexes. La même intégrine peut présenter des spécificités de ligand variables en fonction du type de cellules, et le dysfonctionnement des intégrines est lié à de nombreuses maladies. Le projet MIMIC, financé par l’UE, mène actuellement une étude expérimentale et de calcul informatique complète sur la signalisation des intégrines, qui aboutira à une plateforme pour la conception d’inhibiteurs d’intégrines ciblant des applications thérapeutiques.

Objectif

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.