Gi-regulated signaling pathways in platelets and leukocytes

• Applicants: Professorin Dr. Sandra Beer-Hammer; Dr. Veronika Leiss
• Subject Area: Pharmacology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400989884

Platelets fulfill essential functions in hemostasis as well as in inflammation. Pathophysiologically, thrombosis, embolism and inflammation are closely intertwined and the underlying interactions between platelets and leukocytes are referred to as the thrombo-inflammatory process. Although regulation by G protein-coupled signaling pathways is well documented, the functions and biological consequences of the closely related Gαi isoforms Gαi2 and Gαi3 in platelets as well as in leukocytes remain largely unresolved. Our previous studies show that ablation of Gαi isoforms in leukocytes and platelets leads to a significant reduction of the infarct area in an acute murine model of myocardial ischemia-reperfusion (mI/R) injury. Furthermore, with the single administration of an anti-Gαi2 antibody (Gαi2-Ab) shortly before recanalization of the occluded coronary artery, we also achieved a significant reduction in mI/R damage without affecting hemostasis in each case. We therefore assume that different Gαi-dependent signaling mechanisms in leukocytes and platelets play essential roles in the development of mI/R damage. Following on from our previous findings, we now focus on the mechanisms and functional significance of two selected approaches to reduce murine mI/R damage. (i) Thus, a Gαi2-Ab after ischemia could be an interesting way to significantly reduce I/R damage. The mechanisms such as uptake of the antibody in neutrophils/macrophages and the subsequent inhibitory effects on Gαi2-specific signaling pathways will be identified. (ii) Specific absence of Gαi3 protein in platelets also reduces I/R damage, most likely via non-canonical G protein-dependent signaling pathways and without the risk of increased bleeding susceptibility. Therefore, the Gαi3-regulated signaling pathways responsible for megakaryo-/thrombopoiesis, mitochondrial function and (ROS-induced) mitophagy and for the extent of I/R damage will be elucidated to provide new ideas for therapeutic concepts.

• DFG Programme: Research Grants