Coordination Funds

最近的研究已经确定了代谢网络和信号通路，控制以前未被认识到的调节细胞死亡方式。其中包括铁凋亡，这是一种普遍存在的疾病相关的细胞死亡形式，其特征在于特定的代谢限制和脂质氢过氧化物的铁依赖性积累。铁凋亡的调节元件已被证明与几种细胞代谢过程相关，包括多不饱和脂肪酸（PUFAs）代谢、甲羟戊酸途径、Krebs循环、铁处理和半胱氨酸/谷胱甘肽（GSH）代谢。这些中心代谢途径集中在硒酶谷胱甘肽过氧化物酶4（GPX 4）的关键重要性上，由于其有效减少磷脂双层中所含PUFA中的过氧化物的独特功能，GPX 4如今被认为是铁凋亡的关键调节剂。新出现的证据表明，铁凋亡可能是一种古老的细胞死亡形式，也是一种进化上保守的机制，当功能障碍时，细胞容易过早死亡。此外，已经发现这种高度复杂的细胞死亡途径有助于各种病理状况。这些发现刺激了越来越多的需要了解潜在的遗传和代谢决定因素，调节ferroptosis，以提供新的途径，他们的调制在治疗方面。与SPP相关的小组的合作行动旨在了解不同层次上相关模型系统中潜在的复杂转录和代谢网络，从基本机制到临床前概念。我们进一步努力将从生物化学，细胞和药理学模型系统中获得的知识转化为小鼠和人类的生物体水平。对这些调控网络的更深入了解将最终提供在癌症治疗以及预防或治疗其中铁凋亡起核心作用的退行性疾病的背景下干扰这一过程的可能性。

Recent studies have identified metabolic networks and signalling pathways that control previously unrecognised regulated cell death modalities. Among these is ferroptosis, a prevalent and disease-relevant form of cell death characterised by specific metabolic constraints and an iron-dependent accumulation of lipid hydroperoxides. The regulatory elements of ferroptosis have been shown to be associated with several cellular metabolic processes, including those of polyunsaturated fatty acid (PUFAs) metabolism, mevalonate pathway, Krebs cycle, iron handling and cysteine/glutathione (GSH) metabolism. These central metabolic pathways converge on the pivotal importance of the selenoenzyme glutathione peroxidase 4 (GPX4), which is today regarded as the key regulator of ferroptosis, due of its unique function to efficiently reduce peroxides in PUFAs contained in phospholipid bilayers. Emerging evidence suggests that ferroptosis is likely an ancient form of cell death and an evolutionary conserved mechanism that when dysfunctional renders cells susceptible to premature cell death. Moreover, this highly complex cell death pathway has been found to contribute to various pathological conditions. These findings have stimulated a growing need to understand the underlying genetic and metabolic determinants that regulate ferroptosis in order to provide new avenues for their modulation in a therapeutic context. The collaborative actions of the groups associated with the SPP will aim to understand the underlying intricate transcriptional and metabolic networks in relevant model systems on different levels, ranging from basic mechanisms to pre-clinical concepts. We further strive to translate the knowledge gained from biochemical, cellular and pharmacological model systems to an organismal level in mice and men. A deeper understanding of these regulatory networks will ultimately offer the possibility to interfere with this process in the context of cancer treatment as well as in the prevention or treatment of degenerative conditions where ferroptosis plays a central role.