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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：
10557198
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/10557198
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 Linolenic Acids 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 Tissues Tumor Suppressor Proteins Work cancer cell cancer therapy cell injury dietary dietary excess experience experimental study glutathione peroxidase human disease in vivo Model inhibitor innovation iron metabolism knock-down lipid metabolism lipidomics mitochondrial membrane mitochondrial metabolism model organism 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.

项目总结/文摘