Slc7a11抑制铁死亡的生理效应及机制研究

铁死亡（Ferroptosis）是近年新发现的一种依赖铁的、不同于凋亡的新型细胞死亡方式。我们前期研究发现铁死亡是血色病等铁过载疾病的重要病理机制；同时利用Slc7a11基因敲除小鼠，我们首次揭示了Slc7a11在铁过载诱发铁死亡过程中的重要调控新机制（Hepatology 2017，第一作者）。然而，Slc7a11基因过表达是否抑制铁死亡目前还不清楚。我们初步体外实验结果提示，Slc7a11基因过表达能够明显抑制铁死亡。为了进一步深入研究Slc7a11抑制铁死亡的生理效应及机制，本项目拟通过构建Slc7a11条件性过表达小鼠，并将其与铁过载小鼠进行杂交，以明确在铁过载状态下Slc7a11抑制铁死亡的体内生理效应；通过代谢组学等高通量技术探究Slc7a11调控铁死亡的分子机制。本项目的研究成果将为阐明铁死亡的分子调控机制提供理论依据，为铁过载疾病和铁死亡疾病的防治提供新的靶点和策略。

Ferroptosis is a newly identified iron-dependent, non-apoptotic or necrotic cell death. W recently uncovered a novel regulatory mechanism of ferroptosis in iron overload-related diseases (Hepatology 2017, First author). In addition, we also functionally characterized Slc7a11 as the key regulatory gene in iron induced ferroptosis by using Slc7a11 knockout mice. However, it is currently unknown the roles of Slc7a11 in the process of ferroptosis. Based on our previous study, we hypothesized that Slc7a11 might inhibit ferroptosis. This proposal is designed to test this hypothesis. We aim to investigate the in vivo inhibitory effect of Slc7a11 on iron overload induced ferroptosis by previously successfully established conditional Slc7a11 transgenic mice and genetic iron overload knockout mice in our lab. Notably, our preliminary data show overexpression of Slc7a11 could potently suppress iron-induced ferroptosis in vitro, which sets up a strong rationale for this proposed study. We believe the findings of this proposal, if approved, could not only extend our current knowledge in understanding molecular mechanisms of ferroptosis, but also provide potential novel therapeutic implications for iron overload or ferroptosis related diseases.