Visual Universitätsmedizin Mainz

TRP X2 Redox Signaling

Funding period: 01.09.2015 – 31.08.2018

Project Summary

Activation of platelets is vital to the hemostatic process and a promising drug target to counteract thrombosis. Redox mechanisms significantly contribute to a pro-thrombotic state, because enhanced formation of reactive oxygen species (ROS) provokes an inflammatory milieu. This drives activation of endothelial cells and platelets, favors their interaction and facilities atherothrombosis. Our knowledge about proteins that mediate redox control particularly in platelets is limited. The NADPH oxidase NOX2 has been proposed as major pro-oxidative enzyme. In addition, our preliminary studies demonstrate an equally important role of the anti-oxidant protein PON2. This project addresses their specific functions in platelet activation and thrombosis. To this end, we plan to document NOX2/PON2 contributions to platelet redox homeostasis, calcium signaling, secretion and aggregation. Their impact on multicellular interactions, i.e. platelet adhesion to endothelial cells, will be studied in ex vivo flow chamber experiments and in in vivo thrombosis models. Pharmacologic NOX inhibitors will also be tested as strategy for normalization of redox control. Our research project integrates with other CTH Groups / Platforms or UMC core institutes. We establish major scientific advancement due to the central function of redox control in cell activation and platelet-endothelial interactions in thrombosis.

Principle Investigator

Kleinert
Professor Hartmut Kleinert
Position: Comm. Director of the Institute of Pharmacology, Radiation Safety Officer, Officer for Biological Safety (BBS)

Staff

References

  • Horke S, Xiao J, Schutz EM, Kramer GL, Wilgenbus P, Witte I, Selbach M, Teiber JF (2015) Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N-(3-Oxo-Dodecanoyl)-L-Homoserine Lactone. Infection and immunity 83: 3369-80
  • Krüger M, Amort J, Wilgenbus P, Helmstädter JP, Grechowa I, Ebert J, Tenzer S, Moergel M, Witte I, Horke S (2016) The anti-apoptotic PON2 protein is Wnt/beta-catenin-regulated and correlates with radiotherapy resistance in OSCC patients. Oncotarget