远端上游元件结合蛋白FBP1调控线粒体应激反应的机制研究

线粒体损伤信号可以通过线粒体与细胞核之间的信号交流，重塑染色质结构，诱导线粒体未折叠蛋白反应(UPRmt)，促进修复线粒体损伤，维持细胞稳态平衡。目前，虽然模式动物秀丽线虫中已经有了丰富的研究，但是已发现的调控因子保守性有限，因此高等动物中关于UPRmt的调控机制和相应的生理功能还知之甚少。申请人基于前期研究基础进行遗传筛选，发现远端上游元件结合蛋白FBP1参与UPRmt调控。fbp-2的突变显著抑制线粒体损伤情况下UPRmt的诱导，也抑制线粒体损伤诱导的染色质结构重塑和寿命延长。FBP1是一个结合远端上游元件的转录调控因子，并且在不同物种之间是高度保守的。本项目将聚焦FBP1，结合遗传、生化和细胞生物学的方法，探索FBP1参与调控UPRmt的分子机制，并进一步探索其在哺乳动物细胞中调控线粒体应激的保守性。该研究可以扩展我们对UPRmt转录调控分子机制的理解以及在哺乳动物中生理作用的认识。

Mitochondrial unfolded protein response (UPRmt), which is induced by mitochondrial damage and aiming to relieve proteotoxic stress specifically in mitochondria, is essential for maintaining the normal physiological functions of cells. A number of components and mechanisms of UPRmt regulation has been identified in Caenorhabditis elegans (C.elegans), but the molecular mechanism in mammals and the physiological processes involved in UPRmt regulation remain elusive. From an EMS genetic screen in C.elegans, fbp-2 that encodes a far upstream element binding protein strongly suppressed the UPRmt. We further identified fbp-2 is also involved in regulating chromatin remodeling and longevity during UPRmt. This proposal plans to base on our extensive previous works, combining genetic, biochemical and cellular approaches, aims to explore the specific mechanisms of how fbp-2 is involved in the regulation of UPRmt in C.elegans, and then further explore the conserved functions of UPRmt in cells. This research will extend the understanding of UPRmt mechanisms and the physiological roles of UPRmt in mammals.