Characterization of a novel ferroptosis regulator

新型铁死亡调节剂的表征

• 批准号: 428858739
• 负责人: Dr. Marcus Conrad
• 金额: --
• 依托单位: Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/428858739?language=en
• 关键词: Characterization; novel; ferroptosis; regulator

Ferroptosis is a newly identified cell death modality that has attracted overwhelming interest not only for its contribution to pathological conditions, such as ischemia/reperfusion injury and neurodegeneration, but also as an emerging strategy to eradicate hard to treat tumors. Ferroptosis is negatively regulated by glutathione peroxidase 4 (GPX4) by suppressing the process of phospholipid peroxidation. Therefore, initial attempts have been made to pharmacologically target GPX4 in vivo as a mean to trigger ferroptosis in cancer cells, albeit these approaches have yielded so far only moderate results. This is most likely due to our limited knowledge of the processes that ultimately regulate this form of cell death. In this proposal, we start by presenting the results of an unbiased cDNA overexpression screen aiming to identify genes able to fully complement the loss of GPX4. This approach allowed us to identify a yet-unrecognized oxidoreductase which fully prevents ferroptosis induced by GPX4 deletion or pharmacological inhibition. In this project, we thus aim to characterize how this enzyme is able to bypass the requirement for GPX4 on the molecular level. We will take advantage of a series of state-of-the art methodologies including CRISPR/Cas technology, metabolomics, (oxi) lipidomcis and chemical biology to shed light into the mechanistic details of this novel ferroptosis regulator. Moreover, the in vivo relevance of this pathway will also be assessed through the characterization of two novel mouse models based on the constitutive deletion or the conditional, tissue-specific overexpression of this oxidoreductase. We are convinced that the data generated here will essentially provide a better understanding of the metabolic liabilities sensitizing cells to ferroptosis. In addition, new opportunities will be uncovered to efficiently target this form of cell death with the ultimate goal to identify novel strategies to eradicate cancer cells resistant to standard therapy.

铁凋亡是一种新发现的细胞死亡方式，不仅因其对病理条件的贡献，如缺血/再灌注损伤和神经退行性变，而且作为一种新兴的根除难以治疗的肿瘤的策略，引起了人们的极大兴趣。谷胱甘肽过氧化物酶4（GPX 4）通过抑制磷脂过氧化过程来负调节铁凋亡。因此，已经进行了初步尝试，以在体内靶向GPX 4作为触发癌细胞中的铁凋亡的手段，尽管这些方法迄今为止仅产生了中等的结果。这很可能是由于我们对最终调节这种形式的细胞死亡的过程的了解有限。在这个提议中，我们首先展示了一个无偏见的cDNA过表达筛选的结果，旨在鉴定能够完全弥补GPX 4损失的基因。这种方法使我们能够鉴定出一种尚未识别的氧化还原酶，该氧化还原酶完全防止由GPX 4缺失或药理学抑制诱导的铁凋亡。因此，在这个项目中，我们的目标是表征这种酶如何能够在分子水平上绕过对GPX 4的需求。我们将利用一系列最先进的方法，包括CRISPR/Cas技术，代谢组学，（oxi）lipidomcis和化学生物学，以揭示这种新型铁凋亡调节剂的机制细节。此外，还将通过基于该氧化还原酶的组成性缺失或条件性组织特异性过表达的两种新型小鼠模型的表征来评估该途径的体内相关性。我们相信，这里产生的数据将基本上提供了一个更好的理解代谢负债敏感细胞铁凋亡。此外，将发现新的机会来有效地靶向这种形式的细胞死亡，最终目标是确定新的策略来根除对标准疗法有抗性的癌细胞。