DDIT4-ROS闭环应激控制在毛囊细胞线粒体应激保护中的作用及机制

我国脱发疾病高发，毛囊应激为其共同的病理生理过程。DDIT4是一种细胞应激蛋白，研究表明ROS可以破坏毛囊细胞的线粒体并激发ROS生成的瀑布效应，同时促进DDIT4的表达。我们还发现，毛母质细胞中升高的DDIT4可以反过来抑制ROS的再生。因此我们推测：DDIT4在毛囊应激中发挥着重要作用，可能通过促进TFAM和PGC1α等线粒体转录因子的合成，加强对mtDNA的修复；抑制mTORC1信号，促进线粒体的自噬，以及通过增强细胞内SOD和GPx等还原酶的活性等，加强对ROS的直接清除，从而形成“毛囊应激→ROS↑→DDIT4↑→ROS↓”的闭环控制机制，但具体不清。本课题中我们拟建立不同的ROS应激模型，探讨ROS诱导毛母质细胞高表达DDIT4的机制，以及DDIT4对内源性ROS再生的抑制作用。为深入了解毛囊应激的分子机制，实现对毛囊应激疾病（如斑秃、休止期脱发）的早期临床干预提供依据。

There is high incidence of hair loss diseases in our country. Stress is a typical pathophysiological process during these hair loss diseases. DDIT4 is a cellular stress protein, mainly concentrated inside the mitochondria of hair matrix cells. Previous studies had shown that ROS could induce the expression of DDIT4, as well as DDIT4 is involved in the protection of mitochondria under ROS stress. Our studies further confirmed that the elevated DDIT4 expression would repressed the ROS formation in turn. Therefor, we speculate that there is a special closed-loop feedback of "hair follicle stress→ROS elevation→increased DDIT4 expression→inhibition of ROS regeneration" inside the hair matrix cells to protect mitochondria under ROS stress. In detail, it is speculated that DDIT4 enhances mtDNA repair through mitochondrial transcription factors, such as TFAM, PGC1α, inhibits mTORC1 signal to promote mitochondrial autophagy, and enhances the activity of intracellular reductase such as SOD and GPx to enhance the elimination of ROS, but the specific mechanisms are still unclear. In this project, we propose to establish several ROS stress models for different DDIT4 genotypes of hair matrix cells and explore how ROS induces hair matrix cells to express DDIT4, how DDIT4 protect the mitochondria of hair matrix cells and how it inhibits ROS regeneration in turn. This project will increase our understanding for the stress response of hair diseases, and provides a new basis for the early treatment of various hair follicle stress diseases.