ESR4 - EVOluTION

ESR 4: Angelina Pavlic

Targeted treatment of vascular calcification

Research project

Vascular calcification is an actively regulated process involving vascular smooth muscle cells (VSMC), extracellular vesicles (exosomes) and proteins such as sphingomyelin phosphodiesterase-3 (SMPD3), the vitamin-K dependent Matrix Gla Protein (MGP) and Bone Morphogenetic Proteins (BMP).

The objectives are to develop targeted therapeutic strategies that limit exosome formation and that harness MGP to suppress vascular calcification. Research and training activities of ESR 4 will focus on drug discovery and drug testing (High Content Analysis and preclinical evaluation). ESR 4 will combine in silico approaches utilizing structural bioinformatics methods (identification and priorization of druggable pockets in target proteins like SMPD3, BMP-2 and -4) and Structure-Based Virtual Screening of small molecule inhibitors of calcification. In silico analysis will be performed with technology developed in house and in vitro analyses will be performed using VSMC cultures and the BioHybridTM system (calcification and exosome production as readout). Best hit molecules will be tested in vivo in mouse models of vascular calcification: intimal calcification (apoE-/- on Western Type Diet supplemented with i) vitamin K-nutraceuticals, and ii) warfarin); medial calcification (apoE-/- on Western Type Diet supplemented with high phosphate in combination with unilateral nephrectomy).

Main Supervisor

Name: Chris Reutelingsperger
Email: c.reutelingsperger@maastrichtuniversity.nl

Host Institution

CARIM School for Cardiovascular Diseases
Maastricht University
Universiteitssingel 50
6229 ER Maastricht
The Netherlands

Expected Results

Functional platform of novel therapeutic small molecules to treat vascular calcification.

Planned secondment(s)

NattoPharma, Poland (August 2018): To study small molecules on vitamin K activity.
LMU, Germany (November - December 2018): To study small molecules in experimental atherosclerosis.