Mapping and modulating integrin mediated interactions

Descripción del proyecto

Más cerca de desarrollar tratamientos novedosos para el mal funcionamiento de las integrinas

Las integrinas son una superfamilia de moléculas de adhesión celular que favorecen interacciones estables entre las células y la matriz extracelular. Son receptores que se unen débilmente a las proteínas de la matriz extracelular, algo así como el velcro. Con todo, no solo tienen una función mecánica, ya que también son proteínas de señalización bidireccional y sus actividades, modulación y funciones son bastante complejas. Una misma integrina puede tener diferentes especificidades de ligando en distintos tipos celulares, y la disfunción de las integrinas está relacionada con múltiples enfermedades. El proyecto MIMIC, financiado con fondos europeos, lleva a cabo una investigación experimental y computacional exhaustiva sobre la señalización de las integrinas que permitirá el desarrollo de una plataforma para el diseño de inhibidores de integrinas para aplicaciones terapéuticas.

Objetivo

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.