Understanding dynamics of lipid metabolism and oxidation in ferroptotic cell death programme

了解铁死亡细胞死亡程序中脂质代谢和氧化的动态

• 批准号: 461481616
• 负责人: Dr. Maria Fedorova
• 金额: --
• 依托单位: Zentrum für Membranbiochemie und Lipidforschung
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/461481616?language=en
• 关键词: Understanding; dynamics; lipid; metabolism; oxidation

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.

铁下垂是一种由铁依赖性脂质过氧化（LPO）引起的细胞死亡。上睑下垂成为治疗癌症和退行性疾病的一个有吸引力的治疗靶点。诱导铁下垂与治疗耐药肿瘤有关，而抑制铁下垂对治疗退行性病理有有益作用。因此，在不同组织和病理条件下调节铁下垂电位的能力对于制定特定的治疗策略至关重要。许多研究清楚地表明，脂质代谢和细胞和组织脂质体的特定组成决定了铁下垂的敏感性或抗性。富pufa的细胞膜环境，在缺乏对脂质过氧化的充分控制下，易使细胞迈向铁下垂。此外，细胞发生铁致细胞死亡的承诺将取决于脂质氧化模式以及适应性脂质组重塑。奇怪的是，我们对脂质代谢作为嗜铁细胞死亡的关键调节因子的认识，来自基因筛选和酶表达水平的转录组学测量，而不是来自脂质组本身的评估。为此，需要现代高分辨率脂质组学在脂质物种分子水平上更深入地了解脂质代谢和氧化，以预测铁下垂敏感性，并提出相关的代谢途径，作为支持和抗铁下垂治疗的潜在药理学靶点。该项目旨在通过(1)在细胞和亚细胞水平上绘制诱导和执行铁细胞死亡时脂质组重塑和氧化的动力学图谱，以及(2)通过针对脂质类别和类型特异性途径探索脂质代谢的调节潜力，扩大目前对脂质代谢在铁细胞死亡中的作用的理解。考虑到诱导和抑制铁下垂治疗癌症和退行性疾病的双重兴趣，癌症与正常细胞代谢的明显差异将被解决。最后，神经退行性变、急性肝损伤和肝细胞癌的体内模型将用于验证嗜铁（oxi）脂质组学特征，并将其转化为临床应用。