口腔上皮干细胞存在功能不同的亚群(Cell Stem Cell，2019)，而上皮干细胞功能异常与口腔黏膜的异常增生密切相关。申请人前期通过单细胞测序分析发现口腔白斑病(OLK)中上皮干细胞可分为两个亚群，其中IGFBP2高表达亚群AP1信号通路激活，并与其异常增生度密切相关。为此，我们提出假说：高表达IGFBP2的口腔上皮干细胞亚群通过上调AP1功能，诱发上皮干细胞异常增殖并促进OLK衍进。为验证此假说，拟首先通过临床样本研究验证IGFBP2与OLK异常增生程度的关联；继而通过分离OLK上皮干细胞，从细胞学考察IGFBP2及AP1对上皮干细胞异常增殖调控的作用及其相关分子机制；最后通过转基因小鼠OLK模型及细胞谱系示踪技术，验证IGFBP2通过AP1调控上皮干细胞促进OLK衍进的调控机制。本研究不仅有利于阐明OLK衍进的分子机制，也为优化OLK的防控策略提供依据。

A significant recent finding reported that there is heterogeneity in the oral epithelial stem cells, which could be clustered into several subgroups with different functions, and the imbalance of oral epithelial stem cell function is closely related to oral epithelial dysplasia. Recently, the regulation of stem cells by IGFBP2 has also attracted much attention. Previous research indicated that the oral epithelial stem cell of oral leukoplakia (OLK) could be clustered into two subgroups, and one with the higher expression of IGFBP2 was related to the dysplasia, and the AP1 could be the downstream of IGFBP2. So, we hypothesized that, the subgroup with higher IGFBP2 expression could promote the proliferation and inhibit the differentiation of oral epithelial stem cells via upregulating the AP1, then promote the OLK dysplasia. To validate this hypothesis, firstly the association between IGFBP2, AP1 and the dysplasia of OLK would be confirmed by the large scale OLK samples. Secondly, the epithelial stem cells would be separated from normal and OLK oral tissues and used to investigate the molecular mechanism of IGFBP2 and AP1 on regulating the proliferation and differentiation. Finally, all those findings would be verified with the OLK model of BMI1-cre mouse and cell lineage tracing. This study can not only help to elucidate the molecular mechanism of OLK procession, but also provide the basis for optimizing the strategy of OLK management.