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

Final Report Summary - ATHEROPROTECT (Structure-Function Analysis of the Chemokine Interactome for Therapeutic Targeting and Imaging in Atherosclerosis)

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 functional role has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We have introduced 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 have exploited 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 have been 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 have generated 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 have been used for molecular imaging and chemokine heteromers have been quantified in cardiovascular patients.

We have accomplished the generation of mice with genetic deletion in specific platelet-derived chemokines and have made progress in generating mice expressing chemokine mutants with a defect in heteromeric interactions. We have back-crossed these mouse strains into atherogenic backgrounds and combining genetic deficiency of two chemokines for reconstitution experiments with the obligate heteromers. We have completed the validated mapping, characterization and further biophysical analysis of the chemokine interactome, and have investigated the functional effects of prototypic chemokine heteromers in detail. Finally, we have shown the clinical utility of measuring chemokines with different propensity to from heteromers for risk prediction in cardiovascular disease patients and have further demonstrated the therapeutic potential of disrupting platelet-derived chemokine heteromers using cyclic peptide inhibitors in models of vascular and pulmonary disease.