mTORC1信号通过激活ISR-ATF4导致脂代谢紊乱参与肾纤维化的作用

肾间质纤维化是慢性肾脏病进展的关键因素。肾小管上皮细胞脂代谢紊乱与纤维化密切相关。整合应激反应（ISR）是细胞对损伤的应激适应过程，持续的ISR可引起组织的慢性损伤。活化转录因子4（ATF4）是ISR最具特征的效应元件。作为重要的能量代谢调控途径，mTORC1是激活ISR的关键信号。由此，我们认为mTORC1可通过激活ISR导致小管上皮细胞脂代谢紊乱参与肾间质纤维化的发生发展。本项目以小管上皮细胞为研究对象，分析肾纤维化过程中ISR的变化以及与脂代谢的关系；同时利用近端肾小管上皮细胞Tsc1敲除小鼠和ChIP-seq技术，重点阐明mTORC1-ISR-ATF4调控脂代谢紊乱的机制，以期通过能量代谢新的角度阐明肾间质纤维化的病理机制，为深入认识慢性间质纤维化的机制及未来设计全新的防治方案提供理论基础。

Renal interstitial fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic kidney disease. Lipid metabolic disturbance is closely related to the development of fibrosis. Integrated stress response (ISR) is an adaptive process of eukaryotic cells to diverse stress stimuli, while sustained activation might drive signaling toward chronic damage. Activating transcription factor 4 (ATF4) is the best characterized effector of ISR. In addition to the regulation of cellular metabolism, mTORC1 is also a key activator of ISR. Therefore, the hypothesis is that mTORC1 could regulate lipid metabolism during the progress of fibrosis by activating ISR in proximal tubular epithelial cells. This research project will be set up as follows. Firstly, renal interstitial fibrosis models will be established. We will analyze the changes of ISR during fibrosis and identify the relationship of ISR and lipid metabolism. Secondly, proximal tubular epithelial cells-Tsc1 knockout mice are used to explore the role of mTORC1/ISR in lipid metabolic disturbance. Finally, ChIP-seq will be applied to elucidate the role of ISR-ATF4 in lipid metabolism during renal fibrosis. This study will be helpful to further understand the pathophysiological mechanism of renal interstitial fibrosis and provide theoretical basis for design of new preventive and therapeutic strategies.