Characterizing the Regulation of Ferroptosis

项目摘要/摘要 铁下垂是一种非凋亡性的细胞死亡过程，可以抑制肿瘤的形成和 对疾病病理有贡献。这项研究的长期目标是了解 铁性下垂的分子调控。上睑下垂被认为是通过刻板印象和 不变的脂类依赖机制。然而，在新的初步研究中，我们发现 由独特的基因调节和代谢定义的两种不同形式的铁性下垂的证据 改装。我们发现，由Gpx4酶的直接失活引发的铁下垂需要 脂代谢酶ACSL4的功能。铁性下垂的第二种亚型，由 剥夺半胱氨酸，不需要ACSL4或相关的脂代谢酶，而是依赖于 一组新的基因。在这些新的初步数据的指导下，我们的中心假设是 上睑下垂可以通过两种根本不同的机制来实现。我们将对此进行测试 通过追求三个具体目标提出假设：(I)确定ACSL4和相关脂质的作用 直接抑制Gpx4促进铁性下垂的代谢酶，(Ii)鉴定 两种铁下垂机制在体外和体内的细胞分子特征 以及(Iii)定义调控ACSL4非依赖性铁下垂的基因和过程。 对胱氨酸缺乏的反应。这些研究将使用尖端化学品进行， 遗传学、功能性基因组学、脂体学和成像工具和方法。这项研究将会取得进展 我们对铁性上睑下垂的基本认识，最终目的是改善人类健康。

Project Summary/Abstract Ferroptosis is a non-apoptotic cell death process that can suppress tumor formation and contribute to disease pathology. The long-term objective of this research is to understand the molecular regulation of ferroptosis. Ferroptosis is thought to occur through a stereotypical and invariant lipid-dependent mechanism. However, in new preliminary studies we have uncovered evidence for two different forms of ferroptosis defined by unique genetic regulation and metabolic alterations. We find that ferroptosis triggered by direct inactivation of the enzyme GPX4 requires the function of the lipid metabolic enzyme ACSL4. A second sub-type of ferroptosis, triggered by cystine deprivation, does not require ACSL4 or related lipid metabolic enzymes and instead relies on a novel set of genes. Guided by these new preliminary data, our central hypothesis is that ferroptosis can be executed by two fundamentally distinct mechanisms. We will test this hypothesis by pursuing three specific aims: (i) defining the role of ACSL4 and related lipid metabolic enzymes in promoting ferroptosis in response to direct GPX4 inhibition, (ii) identifying cellular and molecular features that distinguish the two ferroptosis mechanisms in vitro and in vivo, and (iii) defining genes and processes that regulate ACSL4-independent ferroptosis in response to cystine deprivation. These studies will be carried out using cutting-edge chemical, genetic, functional genomic, lipidomic, and imaging tools and methods. This research will advance our fundamental understanding of ferroptosis, with the ultimate goal of improving human health.