跨细胞蛋白质内稳态调控机制

Mechanism of Intercellular Protein Homeostasis Regulation

蛋白质内稳态平衡是受到多级调控的,并不仅限于细胞水平。细胞特定的分区如线粒体(Mito)、内质网(ER),有其独特的调控蛋白质稳态平衡的信号通路。当Mito、ER稳态失衡导致未折叠蛋白在其中累积,会诱导一种适应性的反应,叫做"非折叠蛋白反应"(unfolded protein response, UPR),重建细胞器内部蛋白质稳态平衡。虽然关于Mito和ER蛋白质稳态调控机制已被广泛研究,但对于不同细胞/组织之间是否可以相互影响、协调其Mito、ER UPR来适应环境变化、系统调控物种整体的应激状态这一领域内的重大问题,却一直缺乏研究。基于前期工作基础,本研究将利用线虫和哺乳动物细胞培养两大手段,详细考察跨细胞内稳态调控的分子机制,为治疗衰老、神经退行性疾病、癌症等疾病提供新思路和新靶点。

The protein homeostasis is regulated at multiple scales, not limited at the cellular level. In eukaryotic cells, elaborate signaling pathways are evolved in Mito- chondria （Mito） and Endoplasmic Reticulum （ER） to maintain the protein homeostasis. Disturbance of such homeostasis results in misfolded proteins accumulation in these organelles, and trigger adaptive response termed the Unfolded Protein Response （UPR） in order to cope with the challenge. Much work has been done to understand the UPR in Mito and ER, however, how Mi- to- and ER-UPR function across multiple cells and tis- sues coordinately to deal with the stress in the organism is largely unknown. Here we propose to study the mo- lecular mechanism of cell non-autonomous UPR by u- sing C. elegans and mammalian cell culture system. We anticipate a better understanding of the protein homeo- stasis at the multicellular level, and to provide new therapeutic strategies for related diseases such as aging, neurodegenerative diseases and cancer.