Characterizing the Regulation of Ferroptosis

项目摘要 铁下垂是一种铁依赖的氧化性细胞死亡途径，与肿瘤抑制有关 以及病理性细胞死亡。这一过程在生化上有别于细胞凋亡，经典的 坏死和铁超载导致细胞死亡。铁下垂是如何在分子水平上被调控的 人们对这一水平知之甚少。在初步数据的指导下，本研究将检验假设 铁下垂受雷帕霉素(MTOR)信号转导靶点和中性物质的调节 脂肪合成。此外，使用现有和新发现的抗氧化剂进行的成像研究 铁下垂的抑制剂将定位致命性铁依赖脂反应的细胞部位 铁性下垂期间氧物种(ROS)的积累，并检查这种积累是如何 受mTOR信号和中性脂合成的影响。这些研究将在 借助一种新的延时细胞死亡成像系统和绘制的技术绘制的人体细胞 从化学生物学、遗传学和生物化学。这项研究将促进对 在分子和细胞水平上研究铁下垂，并为将来的体内研究奠定基础 这一鲜为人知的细胞死亡过程。

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.