Characterizing the Regulation of Ferroptosis

项目摘要 铁凋亡是一种铁依赖性的氧化性细胞死亡途径，与肿瘤抑制有关 和病理性细胞死亡。这一过程在生物化学上不同于凋亡， 和铁超负荷诱导的细胞死亡。铁凋亡在分子水平上的调控机制尚不清楚 明白在初步数据的指导下，本研究将测试铁凋亡是 受雷帕霉素（mTOR）信号传导和中性脂质合成的机制靶点调节。 此外，使用现有和新发现的抗氧化剂抑制剂的成像研究 铁凋亡将确定致命的铁依赖性脂质活性氧的细胞位点 (ROS)并检查这种积累如何受到mTOR的影响 信号传导和中性脂质合成。这些研究将在人类细胞中进行， 一种新的延时细胞死亡成像系统和来自化学生物学的技术， 遗传学和生物化学。这项研究将促进对铁凋亡的理解， 分子和细胞水平，并奠定了基础，为今后在体内研究这一穷人 了解细胞死亡过程。

Project Abstract Ferroptosis is an iron-dependent, oxidative cell death pathway implicated in tumor suppression and pathological cell death. This process is biochemically distinct from apoptosis, classic necrosis and iron overload-induced cell death. How ferroptosis is regulated at the molecular level is poorly understood. Guided by preliminary data, this research will test the hypotheses that ferroptosis is regulated by mechanistic target of rapamycin (mTOR) signaling and neutral lipid synthesis. Moreover, imaging studies using existing and newly discovered antioxidant inhibitors of ferroptosis will pinpoint the cellular sites of lethal iron-dependent lipid reactive oxygen species (ROS) accumulation during ferroptosis and examine how this accumulation is affected by mTOR signaling and neutral lipid synthesis. These studies will be performed in human cells with the aid of a novel time-lapse cell death imaging system and techniques drawn from chemical biology, genetics and biochemistry. This research will advance the understanding of ferroptosis at the molecular and cellular levels and lay the foundation for future in vivo studies of this poorly understood cell death process.