ISL-1是成体胰岛β细胞特异性高表达的重要转录因子。我们已证实，ISL-1通过与Set7/9、PDX-1形成复合体，上调Cyclin D1启动子区组蛋白H3K4甲基化水平并增强RNA pol II结合，从而促进β细胞增殖。进一步研究发现，ISL-1还可抑制β细胞凋亡，但具体机制及ISL-1双重功能如何调控却仍未阐明。在本项目中，我们将利用细胞和动物模型，论证ISL-1抑制胰岛β细胞凋亡并维持数量稳定的机制假说：除促进细胞增殖外，ISL-1还可增强Mdm2转录，并以ISL-1/MDM2/P53复合体形式促进P53蛋白质泛素化从而抑制β细胞凋亡。同时，ISL-1 33位丝氨酸磷酸化状态可调控不同复合体形成来实现功能多效性转换，进而从两方面维持β细胞数量稳定。本课题是转录调控与表观遗传修饰相结合来探讨胰岛β细胞凋亡和数量稳定的新视角，其顺利完成可为胰岛相关疾病的基础及临床研究提供新的理论依据。

ISL-1 is an important transcriptional factor which maintains significant high expression level in adult pancreatic islet β cell. It has been demonstrated in our previous study that ISL-1 promotes islet β cell proliferation by up-regulating CyclinD1 expression via forming a complex with Set7/9 and PDX-1. This complex increases the histone H3K4 methylation of the CyclinD1 promoter region and strengthen the binding of RNA pol II. In further study, we find that ISL-1 may inhibit β cell apoptosis. However, the mechanism underlying this process and the switch of this dual function is still unclear. In this study, we will utilize cell and animal model to verify the hypothesis we raised, which may extend the function of ISL-1 in β cell apoptosis and cell count maintenance: in addition to promoting β cell proliferation, ISL-1 is also capable to inhibit β cell apoptosis through up-regulating Mdm2 transcription and increasing P53 protein ubiquitination by ISL-1/MDM2/P53 complex, and these dual function may be regulated by post-translational phosphorylation of 33rd lysine on ISL-1 amino acid sequence. Taken together, this investigation is designed to focus on transcription regulation and epigenetic modification to research β cell apoptosis and cell count maintenance, which is a new perspective for ISL-1 function study. This program will also offer new theoretical evidences for the basic and clinical research of pancreatic islet related diseases.