Induction of Cell Death by Dietary Fatty Acids

膳食脂肪酸诱导细胞死亡

基本信息

批准号：
10116430
负责人：
Jennifer L Watts
金额：
$ 33.34万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116430
关键词：
Adult Affect Anabolism Animal Model Animals Apoptosis Apoptotic Biochemical Caenorhabditis elegans Cancer cell line Cardiolipins Cause of Death Cell Death Cell Death Induction Cell Death Process Cells Cessation of life Consumption Data Development Developmental Biology Diet Dietary Fats Dietary Fatty Acid Disease Embryonic Development Ensure Exposure to Fatty acid glycerol esters Fertility Gene Expression Genes Genetic Germ Cells Germ Lines Gonadal structure Health Heart Diseases Human Ingestion Iron Kidney Failure Lesion Lipid Peroxides Lipids Maintenance Metabolic Metabolism Mitochondria Modeling Molecular Myocardial Ischemia Nematoda Neurodegenerative Disorders Omega-6 Fatty Acids Oxidative Stress Pathway interactions Phenotype Polyunsaturated Fatty Acids Process Production Proteins RNA Interference Reduced Glutathione Regulation Research Research Design Rodent Model Role Site Specificity Sterility System Testing Time Tissues Tumor Suppressor Proteins Work cancer cell cancer therapy cell injury dietary dietary excess experience experimental study gamma-Linolenic Acid glutathione peroxidase human disease in vivo Model inhibitor/antagonist innovation iron metabolism knock-down lipid metabolism lipidomics mitochondrial membrane mitochondrial metabolism monounsaturated fat novel oxidized lipid single-cell RNA sequencing small molecule

项目摘要

Project Summary/Abstract Regulated cell death is essential for proper development and for tissue maintenance throughout adulthood. A recently described form of regulated cell death, ferroptosis, is associated with iron-dependent accumulation of oxidized lipids in the cell. Ferroptosis is biochemically distinct from apoptosis, the most well-studied form of regulated cell death. Ferroptosis is induced by metabolic imbalances within the cell, rather than by induction of pro-death apoptotic proteins. Using the model nematode Caenorhabditis elegans, we discovered an astonishing reduction in fertility upon dietary ingestion of omega-6 polyunsaturated fatty acids. We found that the omega-6 fats caused death of germ cells, but not somatic cells, throughout development, and this dietary- induced cell death was largely independent of the classical apoptosis pathway. We recently found that germ cell death is modulated by small molecule ferroptosis-specific inhibitors and inducers, as well as by manipulating iron levels in cells, establishing that ferroptosis is the mode of cell death induced by dietary fats in C. elegans. In this application, we propose to examine the intracellular sites of lipid peroxide production in the gonad, and characterize new genetic modulators of dietary-induced cell death to elucidate the ways in which ferroptosis is regulated at the tissue, cellular and molecular levels. Modifiers of ferroptosis will be tested in mammalian cancer cell lines. Furthermore, we will dissect the mechanisms of tissue-specificity of dietary- induced ferroptosis and the roles of mitochondrial lipids and metabolism in modulating ferroptosis. Our proposed research will impact both the developmental biology field and the cell death field by further dissecting the mechanisms involved in the novel phenomenon of diet-induced ferroptosis using a genetically tractable animal model. Our project is innovative and unique, because it examines dietary omega-6 fatty acid- induction of ferroptosis in an animal, and it reveals the vulnerability of germ cells to this type of regulated cell death.

项目摘要/摘要受调节的细胞死亡对于整个成年期适当发育和组织维持至关重要。最近描述的调节细胞死亡形式的铁凋亡与铁依赖性积累有关细胞中的氧化脂质。铁凋亡在生化上与凋亡不同，这是最精心研究的形式受调节的细胞死亡。铁凋亡是由细胞内代谢失衡而不是诱导引起的促凋亡蛋白。使用秀丽隐杆线虫的线虫线虫，我们发现了一个饮食摄入omega-6多不饱和脂肪酸后，生育力的惊人降低。我们发现在整个发育过程中，omega-6脂肪在整个发育过程中导致生殖细胞死亡，而不是体细胞的死亡，而这种饮食诱导的细胞死亡在很大程度上与经典凋亡途径无关。我们最近发现胚芽细胞死亡是由小分子铁毒特异性抑制剂和诱导剂以及由操纵细胞中的铁水平，确定铁铁作用是饮食脂肪诱导的细胞死亡方式在秀丽隐杆线虫中。在此应用中，我们建议检查脂质过氧化物产生的细胞内部位性腺，并表征了饮食诱导的细胞死亡的新遗传调节剂，以阐明在组织，细胞和分子水平上调节哪种铁铁作用。铁凋亡的修饰符将被测试在哺乳动物癌细胞系中。此外，我们将剖析饮食的组织特异性机制诱导的铁粒脂质和新陈代谢在调节铁质吞噬作用中的作用。我们的拟议的研究将通过进一步影响发展生物学领域和细胞死亡场解剖饮食诱导的新现象的机制，使用遗传学上可拖动动物模型。我们的项目具有创新性和独特性，因为它检查了饮食中的omega-6脂肪酸 - 诱导动物的铁凋亡，并揭示了生殖细胞与这种调节细胞的脆弱性死亡。