干扰素调控SCF/KIT信号通路在遗传性对称性色素异常症发病中的作用

遗传性对称性色素异常症（DSH）主要临床特征为手足背部对称性色素沉着及色素减退斑，无有效治疗方法。ADAR1是该病的致病基因，但具体机制不明。近期研究发现ADAR1突变可导致内源性干扰素（IFN）增高（Hachung,Cell,2018），电镜观察色素减退区黑素细胞有凋亡现象，我们前期研究表明SCF/KIT可能参与DSH的发病，IFN升高可减少c-KIT表达，而皮损处免疫组化c-KIT无表达。因此推测：ADAR1基因突变后导致干扰素增高，调控SCF/KIT信号通路导致黑素细胞凋亡从而引起临床表型。本课题以SCF/KIT信号通路为主轴，应用CRISPR-Cas9基因敲除、Elisa等基因组学及细胞分子生物学技术检测ADAR1基因突变后IFN的产生及其下游SCF/KIT信号通路调控黑素细胞凋亡和色素代谢的情况。本项目有望阐明DSH色素沉着及色素减退的分子机制，并为探索DSH治疗新靶点奠定基础。

Dyschromatosis Symmetrica Hereditaria (DSH) is a pigmentary genodermatosis characterized by a mixture of hypopigmented and hyperpigmented macules on the dorsum of hands and feet, and there is no effective treatment. ADAR1 is the pathogenic gene of DSH, but the exact pathogenesis is unknown. Recent studies have indicated that ADAR1 mutation can lead to increased production of endogenous interferon (IFN) (Hachung, Cell,2018). Apoptosis of melanocytes can be observed in the hypopigmented area by electron microscope. In preliminary studies, we have also found that SCF and c-KIT were involved in the pathogenesis of DSH. Immunohistochemical staining showed no expression of c-KIT in the lesions of DSH. Based on these findings, we hypothesize that mutation of ADAR1 gene upregulates the production of endogenous interferon, then inhibits the SCF/KIT signaling pathway and leads to melanocyte apoptosis, causing clinical phenotype. In order to identify the molecular mechanism underlying the development of DSH, CRISPR/Cas9 gene-editing system, ELISA and other genomics and molecular biology techniques will be used to detect the production of IFN, the regulation of IFN on SCF/KIT signaling pathway, the apoptosis of melanocytes and the metabolism of pigment when ADAR1 is mutated. This study is expected to identify new strategies and targets for DSH treatment.