Induction of Cell Death by Dietary Fatty Acids

项目摘要/摘要 调节的细胞死亡对于正常发育和整个成年期的组织维持是必不可少的。 最近被描述的一种受调控的细胞死亡形式--铁下垂，与铁依赖的蓄积有关。 细胞内氧化的脂类。铁下垂在生物化学上不同于细胞凋亡，细胞凋亡是研究最深入的形式。 受调控的细胞死亡。铁下垂是由细胞内的代谢失衡引起的，而不是由诱导引起的。 会导致死亡的细胞凋亡蛋白。利用线虫模型线虫，我们发现了一种 饮食摄入omega-6多不饱和脂肪酸会导致生育力的惊人下降。我们发现 在整个发育过程中，omega-6脂肪会导致生殖细胞死亡，但不会导致体细胞死亡，而这种饮食- 诱导的细胞死亡在很大程度上不依赖于经典的细胞凋亡途径。我们最近发现细菌 细胞死亡受小分子铁下垂特异性抑制物和诱导剂的调节，也受 控制细胞中铁的水平，确定铁下垂是由饮食脂肪引起的细胞死亡模式 在线虫中。在这一应用中，我们建议检测细胞内脂质过氧化产物的位置。 性腺，并表征新的饮食诱导细胞死亡的遗传调节因子，以阐明 其中铁下垂在组织、细胞和分子水平上受到调节。将测试铁性下垂的改良剂 在哺乳动物癌细胞系中。此外，我们还将剖析饮食的组织特异性的机制。 诱发性铁下垂及线粒体脂质和代谢在调节铁下垂中的作用。我们的 拟议的研究将对发育生物学领域和细胞死亡领域产生进一步的影响 用遗传学方法剖析饮食诱导的铁下垂这一新现象的机制 易驯服的动物模型。我们的项目是创新和独特的，因为它研究了饮食中的omega-6脂肪酸- 在动物中诱导铁下垂，它揭示了生殖细胞对这种类型的调节细胞的脆弱性 死亡。

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.