Ferroptosis and Polyunsaturated Fatty Acid Metabolism

项目概述：我们研究计划的总体目标是开发化学工具和体内管道 探讨内源性氧化多不饱和脂肪酸(PUFAs)对铁性下垂的调节机制。 铁下垂是最近发现的一种铁依赖的非凋亡性程序性细胞死亡，其特征是 通过增加膜脂过氧化作用。与其他程序性细胞死亡一样，铁下垂具有广泛的影响。 对细胞和胚胎发育、细胞衰老、组织动态平衡和许多疾病的影响。几种关键蛋白质 已经确定了调节上睑下垂的化合物，但上睑下垂和下垂的潜在机制 人们对它的内源性介体知之甚少。这项建议是基于我们以多不饱和脂肪酸为中心的研究 氧化代谢与健康。我们的研究重点是开发新的化学工具来研究 多不饱和脂肪酸代谢产物对人体健康的作用机制。具体地说，我们开发了多种合成方法 制备细胞色素P450(CYP)多不饱和脂肪酸代谢产物。我们还设计并合成了相应的 PUFA小说模仿。我们应用这些合成的代谢物和模拟物来鉴定许多新的生物 多不饱和脂肪酸CYP代谢物的作用。CYP多不饱和脂肪酸生物学效应机制的研究 代谢物，我们在实验室建立了线虫作为一种新的生物模型，因为它拥有大量的遗传工具。 可用于高通量筛选，并具有适应性。所有这些功能都极大地方便了机械化 学习。利用线虫，我们发现内源多不饱和脂肪酸和相应的CYP代谢物诱导 铁性下垂仅见于生殖系和神经元。基于这些发现，我们对此的中心假设 认为多不饱和脂肪酸代谢产物是铁下垂的内源性脂质介质。要取得显著进步 对于这种新颖的程序性细胞死亡的理解，本R35将解决两个问题：1)什么是 铁性下垂的内源性信号分子？2)铁性下垂是如何在特定细胞类型中被调节的 举止？在接下来的五年里，我们将使用多不饱和脂肪酸代谢物、代谢物模拟物和代谢抑制剂 我们将与一种新的模式生物(线虫)及其巨大的遗传工具相结合来合成答案 我们的科学问题是：1)确定触发或抑制铁下垂的内源性多不饱和脂肪酸代谢物；2) 开发一种新的体内平台来描述细胞特异性的铁下垂调节通路。 了解氧化多不饱和脂肪酸代谢产物如何在特定细胞类型中引发铁下垂 铁下垂如何影响人类健康。这项提案的结果将为我们的 未来在多个层面上的研究。已确定的脂质介体和蛋白质靶标将在 用于研究、翻译和机械研究的哺乳动物模型。脂类介体和蛋白质的发现 靶点还允许我们开发治疗与铁下垂相关的疾病的候选药物。已开发的 转基因菌株和体内平台将使我们能够识别新的信号分子或蛋白质靶标 调节细胞型特异型铁下垂。我们将继续开发新的化学工具来研究铁下垂。

Project Summary: The overall goal of our research program is to develop chemical tools and an in vivo pipeline to delineate mechanisms of ferroptosis regulation by endogenous oxidized polyunsaturated fatty acids (PUFAs). Ferroptosis is a recently discovered iron-dependent non-apoptotic programmed cell death that is characterized by an increase in membrane lipid peroxidation. Like other programmed cell death, ferroptosis has a broad impact on cell and embryo development, cell senescence, tissue homeostasis, and many diseases. Several key proteins and compounds that regulate ferroptosis have been identified, but the underlying mechanism of ferroptosis and its endogenous mediators are poorly understood. This proposal is based on our research centered around PUFA oxidative metabolism and health. Our research focuses on generating novel chemical tools to investigate the mechanism of PUFA metabolites on human health. Specifically, we have developed multiple synthetic methods to prepare cytochrome P450 (CYP) PUFA metabolites. We also designed and synthesized the corresponding PUFA novel mimics. We applied these synthesized metabolites and mimics to identify many new biological effects of PUFA CYP metabolites. To investigate the mechanism behind the biological effects of CYP PUFA metabolites, we established C. elegans as a novel biological model in our lab due to the vast genetic tools available and the adaptability for high-throughput screening. All of these features greatly facilitate mechanistic studies. Using C. elegans, we found that endogenous PUFAs and the corresponding CYP metabolites induce ferroptosis only in the germline and neurons. Based on these findings, our central hypothesis for this proposal is that PUFA metabolites are endogenous lipid mediators of ferroptosis. To significantly advance the understanding of this novel programmed cell death, this R35 will address two questions: 1) What are the endogenous signaling molecules of ferroptosis? And 2) How is ferroptosis regulated in a cell type-specific manner? In the next five years, we will use PUFA metabolites, metabolite mimics, and metabolic inhibitors that we will synthesize in combination with a novel model organism (C. elegans) and their vast genetic tools to answer our scientific questions by 1) identifying endogenous PUFA metabolites that trigger or inhibit ferroptosis and 2) developing a novel in vivo platform to delineate cell-specific ferroptosis regulatory pathways. Understanding how oxidized PUFA metabolites trigger ferroptosis in specific cell types will have implications for how ferroptosis may affect human health. The outcomes from this proposal will build a strong foundation for our future research on multiple levels. The identified lipid mediators and protein targets will be further tested in mammalian models for research translation and mechanistic studies. The discovery of lipid mediators and protein targets also allows us to develop drug candidates to treat diseases related to ferroptosis. The developed transgenic strains and in vivo platform will allow us to identify novel signaling molecules or protein targets that regulate cell-type specific ferroptosis. We will continue to develop novel chemical tools to investigate ferroptosis.