Project Details
Projekt
Coordination Funds
Applicant
Dr. Marcus Conrad
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461507177
Ferroptosis is a widespread and disease-relevant form of cell death characterized by specific metabolic constraints and uncontrolled iron-dependent (phospho)lipid peroxidation. The regulatory processes of ferroptosis have been shown to be associated with several cellular metabolic cues, including polyunsaturated fatty acid (PUFA) metabolism, the mevalonate pathway, the Krebs cycle, iron handling and cysteine/glutathione (GSH) metabolism. These important metabolic pathways converge in the central importance of the selenoenzyme glutathione peroxidase 4 (GPX4), which is considered the guardian of ferroptosis due to its unique activity of efficiently reducing peroxides in PUFAs contained in phospholipid bilayers. Since markers of lipid peroxidation have been detected in numerous pathological conditions such as tissue ischemia/reperfusion injury (IRI), neurodegeneration and liver intoxication, ferroptosis may underlie a large number of degenerative disease conditions. On the contrary, the identification of various pharmacologically amenable nodes, such as the cystine-glutamate amino acid antiporter system xC-, GPX4, ferroptosis suppressor protein-1 (FSP1), dihydrofolate reductase (DHFR), GTP cyclohydrolase (GCH1) and 7- dehydrocholesterol reductase (DHCR7), may provide new opportunities for the induction of ferroptosis in the context of certain malignancies. During the first funding period, members of this consortium have made significant and seminal contributions to this rapidly expanding and exciting field of research. The collaborative actions of the groups associated with the SPP will continue to unravel the underlying complex transcriptional and metabolic networks in relevant model systems at different levels, ranging from basic mechanisms including novel regulators of ferroptosis, the chemical process of lipid peroxidation, metabolic rewiring, the role of iron, the identification of novel small molecule modulators of ferroptosis and potential biomarkers to pre-clinical proof-of-concept models. In addition, the SPP 2306 strives to translate the knowledge gained in the first funding period from biochemical, cellular and pharmacological model systems to the organismal level in mice and humans. A deeper understanding of these regulatory networks will ultimately provide the opportunity to intervene in this cell death process in the context of cancer treatment and organ damage as well as in the prevention or treatment of degenerative diseases in which ferroptosis plays a central role.
DFG Programme
Priority Programmes
