Dissecting non-canonical from canonical Gαi-dependent pathways in ischemia- reperfusion injury
Sandra Beer-Hammer & Bettina Weigelin
Cardiovascular diseases and stroke belong to the leading causes of death worldwide. Heart attack and cerebral infarction share similar mechanisms that result in tissue damage. Initially, interruption of the blood supply to the heart or brain tissue by a thrombus or blood clot produces acute oxygen deprivation and triggers a series of events that lead to molecular, structural and metabolic damage. After ischemia, the subsequent reperfusion process promotes a local inflammation mediated by infiltrating immune cells and the production of reactive oxygen species (ROS), exacerbating tissue damage and leading to reperfusion injury.
Elevated numbers of platelet-neutrophil-complexes (PNCs) can be found in the blood of patients suffering from acute myocardial infarction, suggesting that the formation of PNCs is induced by ischemia reperfusion injury (IRI). Furthermore, PNC numbers detected in ischemic myocardial tissue of mice correlate with the severity of IRI-induced tissue damage. It is thought that platelets have a major impact on neutrophil activation and migration into ischemic tissue, and ultimately on the degree of reperfusion injury. Nevertheless, neutrophils are major determinants for the tissue damage.To date, many different components of the G protein signal transduction pathway that govern immune cell migration, in particular neutrophil migration, have been identified.
In this project, we aim to dissect the different Gαi-dependent signaling cascades regulating neutrophil chemotaxis and directional migration that contribute to cerebral IRI. By identifying modulators and interacting partners, we intend to elucidate the partially redundant and distinctive effects of specific Gαi2- and Gαi3-functions on ischemic tissue damage. This will allow us to evaluate the impact of different canonical and non-canonical Gαi-signaling pathways on IRI progression that may help to develop novel strategies to fight stroke.