1 PhD project proposal in the IPP summer call 2020
Coagulation activation and thrombosis are frequently detected in infections, including COVID-19, and cardiovascular diseases. Tissue factor (TF) is a major driver of thrombosis and directly linked to inflammatory processes. How TF expressed by blood and vessel wall cells, and in particular when released via extracellular vesicles (EV), contributes to vascular and thrombo-inflammation remains to be elucidated. We hypothesize that the source of EV and their release mechanism determine the interactions of EV with blood cells and vessel wall in thrombotic inflammation and infections.
PhD project proposal
This project aims to understand how the release mechanisms generating EV from blood (monocytes) and vessel wall cells determine the protein and lipid compositions of EV. The project involves the characterization of how different inflammatory stimuli associated with acute and chronic inflammation influence EV cargo and impact interactions with blood cells and the endothelium in thrombo-inflammation. A particular question is how TF-bearing-EV initiate and disseminate intravascular coagulation processes. The ultimate goal is to develop new diagnostic approaches for measuring functional activities of EV (e.g high sensitivity TF assays) and develop novel methods for imaging EV interactions with vessel wall cells using microfluidic devices in vitro and established thrombosis models in vivo. To this end, an existing large panel of monoclonal antibodies to TF and its binding partners will be used. The long-term perspective of this project is a better definition of the roles of EV in thrombosis, determine their potential to elicit inflammatory cell signaling, and to understand contributions of the coagulation system to pathologies of infectious and other diseases.
Liang HP, Kerschen EJ, Hernandez I, Basu S, Zogg M, Botros F, Jia S, Hessner MJ, Griffin JH, Ruf W, Weiler H. 2015. EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood 125:2845-2854.
Gur-Cohen S, Itkin T, Chakrabarty S, Graf C, Kollet O, Ludin A, Golan K, Kalinkovich A, Ledergor G, Wong E, Niemeyer E, Porat Z, Erez A, Sagi I, Esmon CT, Ruf W, Lapidot T. 2015. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nature Medicine 21:1307-1317.