Skip to main content

Structure-Function Analysis of the Chemokine Interactome for Therapeutic Targeting and Imaging in Atherosclerosis

Ziel

Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients.

Aufforderung zur Vorschlagseinreichung

ERC-2009-AdG
Andere Projekte für diesen Aufruf anzeigen

Gastgebende Einrichtung

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Adresse
Geschwister Scholl Platz 1
80539 Muenchen
Deutschland

Auf der Karte ansehen

Aktivitätstyp
Higher or Secondary Education Establishments
Hauptforscher
Christian Weber (Prof.)
Kontakt Verwaltung
Danny Duhme (Mr.)
EU-Beitrag
€ 2 500 000

Begünstigte (2)

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Deutschland
EU-Beitrag
€ 2 500 000
Adresse
Geschwister Scholl Platz 1
80539 Muenchen

Auf der Karte ansehen

Aktivitätstyp
Higher or Secondary Education Establishments
Hauptforscher
Christian Weber (Prof.)
Kontakt Verwaltung
Danny Duhme (Mr.)
UNIVERSITAETSKLINIKUM AACHEN

Beteiligung beendet

Deutschland
Adresse
Pauwelsstrasse 30
52074 Aachen
Aktivitätstyp
Higher or Secondary Education Establishments
Kontakt Verwaltung
Volker Legewie (Mr.)