血液蛋白参与肝细胞衰老可逆性调控机制的研究

目前已经知道，肝细胞可伴随个体的衰老而衰老，并由此而表现为肝脏功能全面地渐进性衰退。申请人在前期研究中发现，年轻小鼠肝脏微环境可使衰老的肝细胞发生“返老还童”(Hepatology, 2014)。进而采用联体共生小鼠模型证实了年轻血液确实可逆转肝细胞的衰老，并完成了联体小鼠血液蛋白芯片的分析且建立了血液中可能参与肝脏衰老逆转调控的候选蛋白库，也发现了一系列包括GDF15在内的与衰老发生高度相关的候选蛋白。然而，关于这些关联蛋白在衰老肝细胞逆转的调控中发挥什么作用，以及如何发挥作用等方面的细节问题尚未研究。本项目拟采用肝细胞类器官系统和衰老小鼠模型，在发现可以有效调控肝细胞衰老逆转关键因子的基础上，探讨其作用发生的调控机制，进而回答“是否可以通过对血液中个别蛋白质浓度人为干预的方式以减缓或阻止肝脏衰老进程”的科学问题。本项目的开展，有望为肝细胞衰老相关肝脏疾病发生发展的防治研究提供新的思路。

It has known that increased senescent hepatocytes during age contributes to progressively declined in liver functions. In our previous studies, we found that senescent hepatocytes could be reversed when transplanted into the young recipient liver. Furthermore, we performed heterochronic parabiosis model with young and old mice and found that exposed to young blood, not only the senescent hepatocyes were rejuvenation, the functions of liver regeneration and fatty metabolism were also improved in old mice. In addition, protein array were used to investigate the underlying mechanism of young blood effected on senescence reversal. Then according to the reported data of plasma proteome profiles, we conduct the candidate library of plasma proteins that might be involved in senescent rejuvenation and discovered some plasma proteins such as GDF15 was related with aging reversal. However, what and how the candidate plasma proteins regulated in rejuvenation of senescent hepatocytes are need to further study. In this project, hepatocytes orgonoids and old mice model are firstly used to screen and identify the potential proteins contributing to reverse senescent hepatocytes. Then the underlying mechanism of plasma protein regulated on senescent reversal was explored and the improvement of liver regeneration, age-dependent liver diseases were detected by intervention of plasma proteins. Finally, our aim is to answer the scientific question that whether we can alleviate liver aging progress and age-related diseases by intervening the systemic proteins level, for providing the promise strategies on clinic treatment of age-dependent liver diseases.