Development of a lipid-based ferroptosis biomarker for the study of neurodegenerative disease

铁死亡是最近发现的一种基于遗传、生化和代谢特征的细胞死亡方式，与其他形式的细胞死亡完全不同。对铁下垂机制的研究——主要使用肿瘤细胞和小鼠的细胞、遗传和药理学方法——表明，它是治疗难治性和播散性肿瘤以及包括神经变性在内的退行性疾病的一个有吸引力的靶点。虽然脂质过氧化（铁死亡的标志）和铁死亡的关键参与者，如谷胱甘肽过氧化物酶4 （GPX4）和铁死亡抑制蛋白-1，在小鼠和人类之间进化高度保守，但缺乏特异性的铁死亡细胞死亡过程的生物标志物。然而，这些研究不仅对明确证明铁下垂对患者某些疾病背景的影响至关重要，而且还可作为开发新型铁下垂治疗方法的药效学标志物。因此，该项目的主要目标是开发和验证一种基于脂质的生物标志物，该标志物可以单独使用，也可以与细胞死亡标志物联合使用，以监测细胞外体液（如血浆和脑脊液）中铁下垂的程度。具体而言，我们将应用全面的脂质组学方法来评估大脑某些神经元亚群中特异性缺乏GPX4的小鼠，并在患有神经退行性疾病的患者的组织样本中验证这些发现。此外，我们将在复合突变小鼠中询问针对磷脂重塑过程是否是减轻某些神经退行性疾病的有效方法。总之，我们的目标是提供一种完全期待和容易获得的（药效学）生物标志物，用于监测疾病进展和评估磷脂重塑轴，作为开发改善患者神经退行性疾病的新疗法的可利用靶点。

Ferroptosis is a recently described cell death modality entirely different from other forms of cell death based on genetic, biochemical and metabolic traits. Research into the mechanisms of ferroptosis - using mostly cellular, genetic and pharmacological approaches in tumor cells and mice - has revealed that it represents an attractive target to treat therapy-refractory and disseminating tumors, as well as degenerative diseases including neurodegeneration. Although lipid peroxidation, the hallmark of ferroptosis, and the key players of ferroptosis, such as glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein-1, are evolutionary highly conserved between mice and man, biomarkers that are specific to the ferroptotic cell death process are lacking. These are, however, of utmost importance not only to unambiguously demonstrate the contribution of ferroptosis to certain disease contexts in patients, but also to be used as a pharmacodynamic marker for the development of novel ferroptosis-based therapies. Therefore, the main goal of this project is to develop and validate a lipid-based biomarker that either alone or in conjunction with a cell death marker can be harnessed to monitor the extent of ferroptosis in extracellular body fluids such as plasma and cerebrospinal fluid. Specifically, we will apply a comprehensive (oxi)lipidomics approach to assess mice specifically lacking GPX4 in certain neuronal subpopulations of the brain and validate these findings in tissue samples of patients suffering from neurodegenerative disease. Moreover, we will interrogate in compound mutant mice whether targeting the phospholipid remodeling process is a valid approach to mitigate certain neurodegenerative diseases. In summary, we aim to provide an utterly awaited and readily accessible (pharmacodynamic) biomarker for monitoring disease progression and for evaluating the phospholipid remodeling axis as an exploitable target for the development of novel therapies to ameliorate neurodegeneration in patients.