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.
The proposed studies will investigate the regulation of ferroptosis, a new non-apoptotic cell death pathway. This knowledge will enhance our understanding of this fundamental biological process and potentially identify new ways to manipulate this pathway therapeutically.
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