Casein kinase 1 dependent signalling in thrombopoiesis and platelet activation during arterial thrombosis and cardiovascular thrombo-inflammation

• Applicant: Professor Dr. Oliver Borst
• Subject Area: Cardiology, Angiology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549341474

CK1 plays a major role in many different cellular mechanisms regulating cell survival and apoptosis, cytoskeletal reorganization and cell adhesion. Altogether, these mechanisms are of central importance for platelet production and activation, but their role in megakaryocytes (MKs) and platelets (patho-) physiology is virtually unknown. CK1 isoforms are monomeric serine/threonine-selective protein kinases that have distinct functions in various processes such as mitotic checkpoint signaling, apoptosis, immune response and inflammation. CK1α and CK1δ/ε are signaling molecules in multiple hematological malignancies, such as myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML), and several small molecules targeting CK1 have already been evaluated in preclinical and clinical trials. In this study we aim to determine the differential role of casein kinases 1 (CK1) isoforms in intracellular signaling pathways involved in MK maturation, MK polarization and PP formation/thrombopoiesis. Further we will elucidate the role of CK1 isoforms in Ca2+-dependent platelet signaling during activation and vesicle trafficking in occlusive arterial thrombosis and thrombo-inflammatory diseases. To this end, several different in vitro and in vivo approaches will be determined to investigate regulation of MK endomitosis, cytoskeletal organization and polarisation during thrombopiesis. Further we will analyze the impact of CK1 signaling on platelet function in vitro and in vivo during arterial thrombo-inflammation. To circumvent prenatal death and to investigate MK/platelet-specific effects of CK1 isoforms on mechanisms regulating thrombopoiesis, haemostasis and arterial thrombosis in vivo, mice expressing alleles of the different CK1 isoforms flanked with the loxP-Cre excision sequence (Ck1αfl/fl, Ck1δfl/fl, Ck1εfl/fl, Ck1δεfl/fl) were generated to achieve MK/platelet-specific deletion of CK1 isoforms (Ck1αPf4∆/Pf4∆, Ck1δPf4∆/Pf4∆, Ck1εPf4∆/Pf4∆, Ck1δεPf4∆/Pf4∆) using the PF4-Cre recombinase. This study will provide us with further insights into the regulation of platelet formation and potential new therapy options for the treatment of thrombocytopenia and possibly also occlusive thrombo-inflammatory diseases.

• DFG Programme: Research Grants