Project Details
Projekt
Understanding dynamics of lipid metabolism and oxidation in ferroptotic cell death programme
Applicant
Professorin Dr. Maria Fedorova
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461481616
Ferroptosis is a type of cell death driven by iron-dependent lipid peroxidation (LPO). Ferroptosis emerged as an attractive therapeutic target for treating cancer and degenerative diseases. Induction of ferroptosis is relevant for the treatment of therapy-resistant tumors whereas its inhibition showed beneficial effects in addressing degenerative pathologies. Thus, ability to modulate ferroptosis potential in different tissues and pathological conditions is utmost importance for the development of specific therapeutic strategies. Numerous studies clearly established that lipid metabolism and specific composition of cellular and tissue lipidomes determine ferroptosis sensitivity or resistance. PUFA-rich environment of cellular membranes, in the absence of adequate control over lipid peroxidation, predispose cells towards ferroptosis. Moreover, commitment of a cell to undergo ferroptotic cell death will depend on lipid oxidation patterns as well as adaptive lipidome remodeling. Curiously, our knowledge on lipid metabolism as a key regulator of ferroptotic cell death, derived from genetic screens and transcriptomics measurements of enzymes expression levels but not from assessment of lipidome itself. To this end, a deeper understanding of lipid metabolism and oxidation at lipid species molecular level, provided by modern high resolution lipidomics, is required to predict ferroptosis sensitivity and propose relevant metabolic pathways as a potential pharmacological targets for pro- and anti-ferroptotic therapies. The proposed project aims to expand current understanding on the role of lipid metabolism in ferroptosis by (1) mapping dynamics of lipidome remodeling and oxidation upon induction and execution of ferroptotic cell death at cellular and subcellular levels, and (2) exploring modulatory potential of lipid metabolism by targeting lipid class and type specific pathways. Considering dual interest in induction and inhibition of ferroptosis for treating cancer and degenerative disorders, apparent differences in metabolism of cancer vs normal cells will be addresses. Finally, in vivo models of neurodegeneration, acute liver injury and hepatocellular carcinomas will be used to validate ferroptotic (oxi)lipidomics signatures and access their translational potential into clinical applications.
DFG Programme
Priority Programmes
