Descripción del proyecto
Identificación de nuevas dianas para modular la señalización inflamatoria
La manipulación del proceso inflamatorio es una estrategia de tratamiento deseable con aplicaciones en muchas enfermedades. Los científicos del proyecto iRhomADAM, financiado con fondos europeos, se proponen estudiar la metaloproteinasa ADAM17, conocida por escindir y liberar la citocina inflamatoria clave TNFα. El proyecto se centrará en la interacción de la ADAM17 con la iRhom2, una proteína que regula el tráfico, la maduración y la estabilidad de la ADAM17. La información estructural sobre la interacción entre ambas proteínas ayudará a diseñar inhibidores y a probarlos en macrófagos. En conjunto, el proyecto iRhomADAM tiene el potencial de identificar nuevas dianas de la señalización inflamatoria.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
OX1 2JD Oxford
Reino Unido