Project Details
Projekt
Role of Metabolism-induced Ferroptosis Following Solid Organ Transplantation and its Implication for Allograft Survival
Subject Area
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 549821077
Ferroptosis, a non-apoptotic form of programmed cell death, is well known to be induced by iron-dependent lipid peroxidation. Numerous studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases and has been meanwhile extensively described for several forms of ischemia-reperfusion injury (IRI). Whereas pathways for targeting ferroptosis especially in renal IRI have been suggested, nothing is known about ferroptosis in the context solid organ transplantation (SOT). In principle, IRI-induced inflammation during transplantation is a major contributor to allograft outcome involving both donor- and recipient-derived cells. As ferroptosis is deeply intertwined with a diverse array of metabolic pathways triggered by IRI and subsequent alloreactivity, it is therefore imperative to discern the specific role of ferroptosis in shaping the intragraft milieu and to understand whether different leukocytes have differential susceptibility to ferroptosis. This becomes even more relevant as cell based regenerative therapies with e.g. regulatory T cells (Tregs) have emerged as important therapeutic alternatives to reduce standard immunosuppressive regimens. Thus, understanding the role of ferroptosis in the context of Tregs maintenance and effector function is crucial to achieve long-term graft acceptance and tolerance in transplantation. By using state-of-the-art techniques including RNA sequencing, confocal/intravital microscopy, and flow cytometric measurement of metabolic markers we will decipher the impact of ferroptosis in a murine model of kidney transplantation with respect to transplantation-associated risk factors (donor age, IRI) as well as in blood and tissue specimens from transplanted patients. We will address whether targeting of ferroptosis in the donor or in the recipient results in improved outcome post kidney transplantation considering its translational potential into the clinic by testing ferroptosis inhibition in a small animal model of machine perfusion. Collectively, our work will provide a better understanding of how ferroptosis is regulated in the transplantation setting offering prospective therapeutic avenues for potential translation of ferroptosis-targeting therapeutics to clinical organ transplantation.
DFG Programme
Priority Programmes
