利用Jup基因突变小鼠研究Plakoglobin在表皮中的生物学功能

Epidermal integrity is essential for skin functions. It is maintained by adhesive structures, mainly desmosomes and adherens junctions，between keratinocytes. Junction plakoglobin, also known as JUP is the only common component of desmosome and adherens junction. As a constituent of intercellular junctions, it can also regulate gene expression possibly through Wnt signaling pathway. However, the function and molecular mechanism of JUP in epidermis remain unclear. Mutation of JUP causes abnormal intercellular junctions of keratinocytes, which associates with cutaneous diseases such as pemphigus vulgris、epidermolysis bollosa etc.We have generated two genetic modified mouse models with JUP mutation, which have obvious epidermal phenotype. This project will use these mouse models to study JUP function, especially its C-terminus, in intercellular junctions and its potential role in Wnt signaling pathway in epidermis. The ultimate goal of this project is to provide a new perspective in treating patients with JUP mutation related diseases.

表皮主要由角质形成细胞相互连接构成，桥粒和粘着连接是角质形成细胞间连接的基础。Plakoglobin(JUP)是桥粒和粘着连接的重要组成部件，也是唯一在两者中均存在的结构蛋白，既能参与细胞间的机械连接，又能参与Wnt通路调控基因表达。然而，JUP在表皮中的功能及其分子生物学机制尚不清楚。JUP基因突变引起角质形成细胞间连接异常，可导致严重的皮肤疾病，如寻常型天疱疮，大疱性表皮松解症等。前期我们利用基因敲入技术，构建了2种JUP基因突变小鼠，具有明显的皮肤表型。本项目拟在前期研究基础上，通过对突变小鼠的深入研究，探讨JUP在角质形成细胞间连接和Wnt信号转导通路中所发挥的作用及其分子生物学机制，同时研究JUP蛋白C-端的分子生物学功能。本研究将有助于阐明JUP基因突变引起表皮结构异常的分子生物学机制，为JUP基因突变患者治疗提供新的靶点和途径。

Plakoglobin(JUP)是桥粒和粘着连接的重要组成部件，也是唯一在两者中均存在的分子。JUP基因突变引起角质细胞间连接异常，可导致严重的皮肤疾病。“Naxos”病患者因JUP基因突变，角质细胞表达C-端缺失的JUP蛋白，导致“掌跖角质化”。我们模拟“Naxos”病JUP突变，构建了2种基因突变小鼠，PGM小鼠具有明显的皮肤表型。本项目通过对突变小鼠的深入研究，探讨了JUP在角质细胞间连接和Wnt信号转导通路中所发挥的作用及其分子生物学机制，同时研究JUP蛋白C-端的分子生物学功能。本研究证实，C-端缺失并不影响JUP蛋白发挥其在表皮中的生物学功能，JUP蛋白表达量下降将显著影响小鼠表皮的形态及功能。