The fundamentals of cardiovascular calcification: from cells to therapy

Introduction

With this project, I propose to identify fundamental mechanisms of cardiovascular calcification (CVC) and new therapeutic targets using zebrafish as a model system. CVC, characterized by progressive calcification of the soft tissue causing impaired blood circulation, is a frequent form of cardiovascular disease.

Background

Because the pathophysiology of CVC is highly heterogeneous, the exact cell types and signaling pathways triggering tissue calcification are still unknown, thus limiting therapy options. Most studies on CVC rely on in vitro systems, which fail to reproduce the multicellular environment, or mammalian in vivo models, which are limited for live imaging and high-throughput analyses.

Research Proposal

By combining my expertise in cardiovascular research and bone biology, I propose to use zebrafish as a model to elucidate the multifactorial mechanisms of CVC, focusing on different developmental stages and cardiovascular tissues.

Aim 1

1. I will use a broad array of zebrafish genetic models to characterize the cellular dynamics, molecular mechanisms, and functional impact of CVC in vivo.
2. I will also study the role of specific cell populations present in regenerating valves and human valve implants with CVC.

Aim 2

1. I propose to identify new local and systemic therapeutic strategies to block/reverse CVC, taking advantage of the zebrafish's amenability for genetic manipulation and high-throughput screening.
2. I will recruit bone-degrading cells to the CVC site and determine their potential to reverse tissue calcification.
3. Moreover, I will select a short list of small molecules identified in a large-scale screen in zebrafish and will test their therapeutic potential in cardiovascular cells derived from hiPSCs of CVC patients.

Conclusion

Altogether, with this interdisciplinary approach, I expect to bring a new perspective on the mechanisms and therapeutic targets to block/reverse CVC, which could have a considerable impact on the European population, severely affected by these diseases.