Ferroptosis and Polyunsaturated Fatty Acid Metabolism

铁死亡和多不饱和脂肪酸代谢

• 批准号: 10661780
• 负责人: Kin Sing Stephen Lee
• 金额: $ 39.13万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661780
• 关键词: Affect; Apoptosis; Biological; Biological Models; Cell Aging; Cell Respiration; Cells; Chemicals; Cytochrome P450; Data; Disease; Embryonic Development; Foundations; Genetic; Goals; Health; Homeostasis; Human; Investigation; Iron; Lipid Peroxidation; Mediator; Membrane Lipids; Metabolic; Methods; Modeling; Neurons; Outcome; Physiology; Polyunsaturated Fatty Acids; Proteins; Regulation; Regulatory Pathway; Research; Role; Signaling Molecule; Signaling Protein; Testing; Tissues; Transgenic Organisms; Translational Research; analytical tool; cell type; design; drug candidate; fatty acid metabolism; high throughput screening; in vivo; inhibitor; lipid mediator; model organism; novel; programs; tool

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.

项目摘要：我们研究计划的总体目标是开发化学工具和体内管道 描述内源性氧化多不饱和脂肪酸（PUFA）调节铁死亡的机制。 铁死亡是最近发现的一种铁依赖性非凋亡性程序性细胞死亡，其特征是 通过膜脂过氧化的增加。与其他程序性细胞死亡一样，铁死亡具有广泛的影响 细胞和胚胎发育、细胞衰老、组织稳态和许多疾病。几种关键蛋白质 调节铁死亡的化合物已被鉴定，但铁死亡的潜在机制和 其内源性介质知之甚少。该提案基于我们以 PUFA 为中心的研究 氧化代谢与健康。我们的研究重点是生成新型化学工具来研究 PUFA代谢物对人体健康的作用机制。具体来说，我们开发了多种合成方法 制备细胞色素 P450 (CYP) PUFA 代谢物。我们还设计并合成了相应的 PUFA小说模仿者。我们应用这些合成的代谢物和模拟物来识别许多新的生物 PUFA CYP 代谢物的影响。研究 CYP PUFA 生物效应背后的机制 代谢物，由于拥有大量的遗传工具，我们在实验室建立了秀丽隐杆线虫作为一种新颖的生物模型 的可用性和高通量筛选的适应性。所有这些功能都极大地促进了机械化 研究。使用秀丽隐杆线虫，我们发现内源性 PUFA 和相应的 CYP 代谢物诱导 铁死亡仅发生在种系和神经元中。基于这些发现，我们对此的中心假设 建议认为 PUFA 代谢物是铁死亡的内源性脂质介质。显着推进 为了理解这种新颖的程序性细胞死亡，该 R35 将解决两个问题：1）什么是 铁死亡的内源性信号分子？ 2）铁死亡是如何在细胞类型特异性中受到调节的 方式？未来五年，我们将使用PUFA代谢物、代谢物模拟物和代谢抑制剂 我们将结合一种新型模式生物（秀丽隐杆线虫）及其庞大的遗传工具来合成来回答这个问题 我们的科学问题是通过 1) 识别触发或抑制铁死亡的内源性 PUFA 代谢物以及 2) 开发一种新颖的体内平台来描绘细胞特异性铁死亡调节途径。 了解氧化的 PUFA 代谢物如何引发特定细胞类型的铁死亡将对 铁死亡如何影响人类健康。该提案的成果将为我们的 未来多层次的研究。已确定的脂质介质和蛋白质靶标将在以下方面进行进一步测试 用于研究翻译和机制研究的哺乳动物模型。脂质介质和蛋白质的发现 目标还使我们能够开发候选药物来治疗与铁死亡相关的疾病。所开发的 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 调节细胞类型特异性铁死亡。我们将继续开发新的化学工具来研究铁死亡。