Def-Rybp-Capn3a新通路对斑马鱼肝脏发育调控机制的研究

肝脏正常发育是其发挥正常功能的基础。核仁蛋白Def是申请人所在研究团队率先研究并命名的，def的缺失会导致斑马鱼肝脏发育不全。我们之前报道过Def能与半胱氨酸蛋白酶Capn3b互作并将后者运输到核仁中行使蛋白降解的功能。capn3a是capn3b的同源基因，有趣的是，我们发现Def不能与Capn3a互作，但是Capn3a而不是Capn3b的敲降可以导致斑马鱼肝脏的发育异常。此外，我们发现泛素结合蛋白Rybp可以分别和Capn3a以及Def互作，但不可以和Capn3b互作。据此，我们推测机体内或将存在一个全新的Def-Rybp-Capn3a通路在肝脏发育等生命过程中发挥作用。本项目将研究Rybp与Def和Capn3a互作的分子基础，并利用相关斑马鱼突变体深入研究Def-Rybp-Capn3a通路的生物学功能及其机制。研究结果将加深人们对肝脏发育的认识，并为相关肝脏疾病的诊治提供理论指导。

Liver plays an important role in human health and organ homeostasis. Loss of function of the nucleolar protein Def, which was first studied and named by the applicant's research team, leads to liver hypoplasia in zebrafish. We previously reported that Def interacts with the cysteine protease Capn3b and further transports it into the nucleolus, where Capn3b induces protein degradation. Capn3a is a homologous gene of Capn3b. Interestingly, though Capn3a is not a Def interaction protein, deletion of Capn3a, rather than Capn3b, leads to abnormal liver development in zebrafish. In addition, we found that a ubiquitin binding protein, Rybp, could interact with Capn3a and Def respectively, but not with Capn3b. Therefore, we speculate that there should be a new Def-Rybp-Capn3a pathway that plays an important role in liver development and other life processes. This proposal will focus on studying the interaction mechanism between Rybp and Def and between Rybp and Capn3a. Meanwhile, we will use relevant zebrafish genetic mutants to study the biological functions of the Def-Rybp-Capn3a pathway. This research work will add valuable insight into the regulatory network underlying liver development, and the knowledge obtained will help to guide the diagnosis/treatment of the related liver diseases.