Targeting megakaryocytes to generate reparative platelets in atherothrombosis

1 PhD project offered in the IPP winter call 2022/2023

Scientific Background

Cardiovascular diseases (CVD) cause one third of all deaths worldwide. With increasing incidence of metabolic diseases in industrialized nations and emerging countries, a further global increase in cardiovascular diseases is expected in the future. Atherothrombosis is the main cause of heart attack and stroke and it was recognized early on that platelets play an important role, which is why, in addition to the treatment of hyperlipidemia, e.g. with statins, dual antiplatelet therapy (DAPT) is now an important part of the standard treatment. Despite advances in the treatment of atherothrombosis, thrombotic events continue to occur even with optimal therapy. The aim of this project is to develop a novel therapeutic approach that focuses on the thromboinflammatory component of atherothrombosis. Together with our project partners, we want to generate anti-inflammatory platelets with an increased regenerative and reparative potential through RNA-based targeting of platelet precursors (megakaryocytes).

PhD Project: Targeting megakaryocytes to generate reparative platelets in atherothrombosis

The aim of this project is the development of a novel therapeutic approach that specifically addresses the thrombo-inflammation of atherothrombosis where multiple platelet functions are relevant: the local release of mediators stored in platelet granules and the stimulation/regulation of immune cells for wound healing and repair of the injured vessel wall. Together with our project partners, we aim to generate anti-inflammatory, reparative platelets by RNA-based targeting of platelet precursors (megakaryocytes). In the first project phase, our project partners will optimize nanodimensional lipid and polymer formulations for the specific targeting of megakaryocytes which will then be loaded with mRNA of selected targets. Using primary cell cultures of murine megakaryocytes and human iPSC-derived megakaryocytes, the candidate will investigate successful targeting of the megakaryocytes and transfer of the target proteins into mature platelets using flow cytometry and confocal microscopy. In the second phase of the project, we are planning in vivo experiments to verify successful megakaryocyte targeting in mice and to investigate the influence on atherothrombosis in relevant mouse models. In the long term, we plan to establish megakaryocyte/bone marrow targeting using mRNA nanoparticles as a new form of therapy and to investigate it in clinical studies.

If you are interested in this project, please select Deppermann as your group preference in the IPP application platform.

Publications relevant to this project

Deppermann et al., J. Clin. Invest. 2013

Deppermann et al.,Blood 2017

Mandel et al., Int. J. Mol. Sci. 2022

Ridker et al., N. Engl. J. Med. 2017

Nuhn et al. Bioconjugate Chem. 2018

Nuhn et al., Macromol. Rapid Commun. 2016

Contact Details

Jun.-Prof. Dr. Carsten Deppermann

www.cth.de

www.plateletlab.de

Email

Website

Prof. Dr. Wolfram Ruf

www.cth.de

Email

Website