1 PhD project offered in the IPP summer call Molecular Biomedicine & Ageing

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 has been established 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 in the bone marrow (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 component 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 project preference in the IPP application platform.

Publications relevant to this project

Deppermann C, Cherpokova D, Nurden P, Schulz JN, Thielman I, Kraft P, Vögtle T, Kleinschnitz C, Dütting S, Krohne G, Eming SA, Nurden AT, Eckes B, Stoll G, Stegner D, Nieswandt B (2013) Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice. J Clin Invest. 123 (8):3331-3342 Link

Deppermann C, Kraft P, Volz J, Schuhmann MK, Beck S, Wolf K, Stegner D, Stoll G, Nieswandt B (2017) Platelet secretion is crucial to prevent bleeding in the ischemic brain but not in the inflamed skin or lung in mice. Blood 129 (12):1702-1706. Link

Mandel J, Casari M, Stepanyan M, Martyanov A, Deppermann (2022) Beyond Hemostasis: Platelet Innate Immune Interactions and Thromboinflammation. Int J Mol Sci 23(7):3868 Link

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group (2017) Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 377(12):1119-1131. Link

Nuhn L, Bolli E, Massa S, Vandenberghe I, Mohavedi K, Devreese B, Van Ginderachter JA, De Geest BG (2018) Targeting Protumoral Tumor-Associated Macrophages with Nanobody-Functionalized Nanogels through Strain Promoted Azide Alkyne Cycloaddition Ligation. Bioconjug Chem. 29(7):2394-2405. Link

Nuhn L, Kaps L, Diken M, Schuppan D, Zentel R (2016) Reductive Decationizable Block Copolymers for Stimuli-Responsive mRNA Delivery. Macromol Rapid Commun. 37(11):924-933. Link